NZ616270B2 - Imidazopyridazines as akt kinase inhibitors - Google Patents

Abstract

Imidazo[1,2-B]pyridazines of formula (I) a process for their production and the use thereof. Examples of compounds of formula (I) are: 1-[4-(6-Methyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]-cyclobutanamine; 1-[4-(6-Ethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]-cyclobutanamine; 1-{4-[3-Phenyl-6-(trifluoromethyl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamine and Ethyl 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate. The compounds are useful in treating benign neoplasia, malignant neoplasia and breast cancer. yl-6-(trifluoromethyl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamine and Ethyl 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate. The compounds are useful in treating benign neoplasia, malignant neoplasia and breast cancer.

Description

IMIDAZOPYRIDAZINES AS AKT KINASE INHIBITORS Field of application of the invention The invention relates to substituted opyridazines, a process for their production and the use thereof.

Known technical background Cancer is the second most prevalent cause of death in the United States, causing 450,000 deaths per year. While substantial progress has been made in identifying some of the likely environmental and tary causes of cancer, there is a need for additional therapeutic modalities that target cancer and related diseases. In particular there is a need for therapeutic methods for treating diseases associated with dysregulated growth / proliferation.

Cancer is a complex disease arising after a selection process for cells with acquired functional capabilities like enhanced survival / resistance towards apoptosis and a limitless proliferative potential. Thus, it is preferred to develop drugs for cancer therapy addressing distinct features of established tumors.

One pathway that has been shown to mediate important survival signals for mammalian cells comprises receptor tyrosine kinases like et-derived growth factor receptor (PDGF-R), human mal growth factor 2/3 receptor (HER2/3), or the insulin-like growth factor 1 or (lGF-fR). After activation the respectives by ligand, these ors activate the phoshatidylinositol 3- kinase (Pi3K)/Akt pathway. The tidylinositol 3-kinase (Pi3K)/Akt protein kinase y is central to the l of cell growth, proliferation and survival, driving progression of tumors. Therefore within the class of serine-threonine ic signalling kinases, Akt (protein kinase B; PKB) with the isoenzmyes Akt1 (PKBoc), Akt2 (PKB B) and Akt3 (PKB y) is of high interest for therapeutic intervention. Akt is mainly activated in a Pi3-kinase dependent manner and the activation is regulated through the tumor suppressor PTEN (phosphatase and tensin homolog), which works essentially as the functional antagonist of Pi3K.

The Pi3K/Akt pathway regulates fundamental cellular functions (e.g. transcription, translation, growth and survival), and is ated in human diseases including diabetes and cancer. The pathway is frequently overactivated in a wide range of tumor entities like breast and te carcinomas. Upregulation can be due to overexpression or constitutively activation of receptor tyrosine kinases (e.g. EGFR, HER2/3), which are upstream and involved in its direct activation, or gain- or loss-of-function mutants of some of the components like loss of PTEN. The pathway is targeted by genomic tions including mutation, amplification and rearrangement more frequently than any other pathway in human cancer, with the possible exception of the p53 and retinoblastoma pathways. The alterations of the Pi3K/Akt pathway trigger a cascade of biological events, that drive tumor ssion, survival, angiogenesis and metastasis. tion of Akt kinases promotes increased nutrient , converting cells to a glucose-dependent metabolism that redirects lipid precursors and amino acids to anabolic processes that support cell growth and proliferation. These metabolic phenotype with overactivated Akt lead to malignancies that y a metabolic conversion to aerobic glycolysis (the Warburg effect). In that respect the Pi3K/Akt pathway is discussed to be central for survival despite unfavourable growth conditions such as glucose depletion or hypoxia.

A further aspect of the activated Pl3K/Akt pathway is to protect cells from programmed cell death ("apoptosis") and is hence considered to transduce a survival signal. By acting as a modulator of anti-apoptotic signalling in tumor cells, the Pi3K/Akt pathway, ularly Akt itself is a target for cancer therapy.

Activated Akt orylates and regulates several targets, e.g. BAD, GSK3 or FKHRL1, that affect ent signalling ys like cell survival, protein synthesis or cell movement. This Pi3K/Akt pathway also plays a major part in resistance of tumor cells to conventional anti-cancer therapies. Blocking the Pi3K/Akt pathway could therefore aneously inhibit the eration of tumor cells (e.g. via the inhibition of the metabolic effect) and sensitize towards optotic .

Akt inhibition selectively sensitized tumor cells to apoptotic stimuli like Trail, Campthothecin and Doxorubicin. Dependent on the genetic background / molecular apperations of tumors, Akt inhibitors might induce apoptotic cell death in monotherapy as well.

Thus Akt seems to be a suitable target for the treatment of .

Various publications exist relating to Akt inhibiting compounds such as e.g. WO 2009/148887, , W02010104933, W02010114780, W0201 5.

In a recent disclosure, Y. Li et al (Bioorg. Med. Chem. Lett. 2009, 19, 834-836 and cited references therein) detail the difficulty in finding l Akt inhibitors.

The potential application of Akt inhibitors in multiple disease settings, such as for example, cancer, makes the provision of new Akt inhibitors to those tly available highly desirable.

Description of the invention A solution to the above m is the provision of alternative Akt inhibitors. It has now been found that the new lmidazopyridazine compounds, which are described in detail below, are Akt inhibitors suitable for the ent of cancer..

In accordance with a first aspect, the invention relates to compounds of formula (I) in which R1 is en, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(O)OR8, C(O)(1-6C-alkyl), NHC(O)(1-6C-alkyl), NHS(O)2R11, NHC(O)NHR11 ,-S(O)n 6C-alkyl, -S(O)2NR5R6 or a group selected from 1-6C-alkyl, 1-6C-alkoxy, 3-7C- lkyl, aryl, heteroaryl, -(1-6C-alkyl)-aryl, -(1-6C-alkyl)-heteroaryl, -O-(3-7C- cycloalkyl), -O-aryl, 7C-heterocyclyl), -O-heteroaryl, -O-(1-GC-alkyl)- heteroaryl, -O-(1-GC-alkyl)-(3-7C-heterocyclyl), -O-(1-6C-alkyl)-aryl, 2—6C- alkenyl, 2—6C-alkynyl, wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from: hydroxy, n, 1-6C-alkyl, aloalkyl, lkoxy, -NR8R9, cyano, - C(O)NR8R9, -C(O)OR10, -NHC(O)R11, -NHC(O)NHR11, -NHS(O)2R11, 3 cycloalkyl, 3-7C-heterocyclyl, aryl, R2 is hydrogen, hydroxy, NR5R6, halogen, cyano, R9), C(O)OR8, C(O)(1-6C-alkyl), NHC(O)(1-6C-alkyl), NHS(O)2R11, NHC(O)NHR11 ,-S(O)n GC-alkyl, -S(O)2NR5R6 or a group selected from 1-GC-alkyl, 1-GC-alkoxy, 3-7C- cycloalkyl, aryl, heteroaryl, -(1-6C-alkyl)-aryl, -(1-GC-alkyl)-heteroaryl, -O-(3-7C- cycloalkyl), -O-aryl, 7C-heterocyclyl), -O-heteroaryl, -O-(1-GC-alkyl)- heteroaryl, -O-(1-GC-alkyl)-(3-7C-heterocyclyl), -O-(1-6C-alkyl)-aryl, 2—6C- alkenyl, 2—6C-alkynyl, wherein said group being optionally substituted, one or more times, identically or differently, with a tuent selected from: hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy, -NR8R9, cyano, - C(O)NR8R9, R10, -NHC(O)R11, -NHC(O)NHR11, -NHS(O)2R11, 3-7C- heterocyclyl, aryl, R3 is en, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(O)OR8, C(O)(1-6C-alkyl), 2R11, NHC(O)NHR11 - S(O)n6C-alkyl, - S(O)2NR5R6 or a group selected from 1-GC-alkyl, 1-GC-alkoxy 3-7C-cycloalkyl, aryl, heteroaryl, -(1-6C-alkyl)-aryl, -(1-6C-alkyl)-heteroaryl, -O-(3-7C-cycloalkyl), -O-aryl, -O-(3-7C-heterocyclyl), -O-heteroaryl, -O-(1-GC-alkyl)-heteroaryl, -O-(1- GC-alkyl)-(3-7C-heterocyclyl), -O-(1-6C-alkyl)-aryl, NHC(O)(1-6C-alkyl), 2—6C- alkenyl, 2—6C-alkynyl, wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from: hydroxy, halogen, lkyl, 1-4C-haloalkyl, 1-6C-alkoxy, -NR8R9, cyano, - C(O)NR8R9, -C(O)OR10, -NHC(O)R11, -NHC(O)NHR11, -NHS(O)2R11, 3-7C- heterocyclyl, aryl, R4 is phenyl which is optionally substituted one, two or three times, identically or differently, with a halogen atom; R5 is hydrogen, 1-6C-alkyl, R6 is hydrogen, 1-6C-alkyl, R8 is hydrogen, 1-6C-alkyl which optionally is substituted with hydroxy, R9 is hydrogen, 1-6C-alkyl, R10 is en, 1-6C-alkyl, R11 is hydrogen, 1-6C-alkyl, X, Y is CH2; n is 0, 1, 2; or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

In accordance with a second aspect, the invention relates to compounds of formula (I), wherein R1 is hydrogen, hydroxy, NR5R6, halogen, cyano, R9), C(O)OR8, C(O)(1-6C-alkyl), NHC(O)(1-6C-alkyl), NHS(O)2R11, NHC(O)NHR11 ,-S(O)n- 1-6C-alkyl, NR5R6 or a group selected from 1-6C-alkyl, 1-6C-alkoxy, 3- 7C-cycloalkyl, aryl, heteroaryl, -(1-6C-alkyl)-aryl, -(1-6C-alkyl)-heteroaryl, -O- (3-7C-cycloalkyl), -O-aryl, -O-(3-7C-heterocyclyl), -O-heteroaryl, -O-(1-6C- alkyl)-heteroaryl, -O-(1-6C-alkyl)-(3-7C-heterocyclyl), -O-(1-6C-alkyl)-aryl, 2- 6C-alkenyl, 2-6C-alkynyl, wherein said group being optionally substituted, one or more times, cally or differently, with a substituent selected from: hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy, -NR8R9, cyano, - C(O)NR8R9, -C(O)OR10, -NHC(O)R11, -NHC(O)NHR11, -NHS(O)2R11, 3- 7C-heterocyclyl, aryl, R2 is en, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(O)OR8, C(O)(1-6C-alkyl), (1-6C-alkyl), NHS(O)2R11, NHC(O)NHR11 n- 1-6C-alkyl, -S(O)2NR5R6 or a group selected from 1-6C-alkyl, lkoxy, 3- 7C-cycloalkyl, aryl, heteroaryl, -alkyl)-aryl, -(1-6C-alkyl)-heteroaryl, -O- (3-7C-cycloalkyl), -O-aryl, -O-(3-7C-heterocyclyl), -O-heteroaryl, -O-(1-6C- alkyl)-heteroaryl, -O-(1-6C-alkyl)-(3-7C-heterocyclyl), 6C-alkyl)-aryl, 2- 6C-alkenyl, 2-6C-alkynyl, wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from: hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, lkoxy, -NR8R9, cyano, - C(O)NR8R9, -C(O)OR10, -NHC(O)R11, )NHR11, -NHS(O)2R11, 3- 7C-heterocyclyl, aryl, R3 is hydrogen, hydroxy, NR5R6, n, cyano, CO(NR8R9), C(O)OR8, C(O)(1-6C-alkyl), NHC(O)(1-6C-alkyl), NHS(O)2R11, NHR11 , -S(O)n- 1-6C-alkyl, -S(O)2NR5R6 or a group selected from 1-6C-alkyl, 1-6C-alkoxy, 3- 7C-cycloalkyl, aryl, heteroaryl, -(1-6C-alkyl)-aryl, -(1-6C-alkyl)-heteroaryl, -O- (3-7C-cycloalkyl), -O-aryl, -O-(3-7C-heterocyclyl), -O-heteroaryl, -O-(1-6C- alkyl)-heteroaryl, -O-(1-6C-alkyl)-(3-7C-heterocyclyl), -O-(1-6C-alkyl)-aryl, 2- 6C-alkenyl, 2-6C-alkynyl, wherein said group being optionally substituted, one or more times, cally or differently, with a substituent selected from: hydroxy, n, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy, -NR8R9, cyano, - C(O)NR8R9, -C(O)OR10, -NHC(O)R11, -NHC(O)NHR11, -NHS(O)2R11, 3- 7C-heterocyclyl, aryl, R4 is phenyl which is optionally substituted one, two or three times, identically or ently, with a halogen atom; R5 is hydrogen, 1-6C-alkyl, R6 is hydrogen, 1-6C-alkyl, R8 is hydrogen, 1-6C-alkyl, R9 is en, 1-6C-alkyl, R10 is hydrogen, 1-6C-alkyl, R11 is hydrogen, lkyl, X, Y is CH2; n is 0, 1, 2; or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

Another aspect of the invention relates to compounds of formula (I), wherein R1 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(O)OR8, C(O)(1-3C-alkyl), NHC(O)(1-6C-alkyl), NHS(O)2R11, NHC(O)NHR11 ,-S(O)n- 1-3C-alkyl, NR5R6 or a group selected from 1-3C-alkyl, 1-3C-alkoxy, 3- loalkyl, aryl, heteroaryl, -(1-3C-alkyl)-aryl, -(1-3C-alkyl)-heteroaryl, -O- cycloalkyl), -O-aryl, -O-(3-6C-heterocyclyl), -O-heteroaryl, -O-(1-3C- alkyl)-heteroaryl, -O-(1-3C-alkyl)-(3-6C-heterocyclyl), -O-(1-3C-alkyl)-aryl, 2- 3C-alkenyl, 2-3C-alkynyl, n said group being optionally substituted, one or more times, identically or differently, with a substituent selected from: hydroxy, halogen, 1-3C-alkyl, 1-3C-haloalkyl, 1-3C-alkoxy, -NR8R9, cyano, - C(O)NR8R9, -C(O)OR10, -NHC(O)R11, -NHC(O)NHR11, -NHS(O)2R11, 3 cycloalkyl, 3-6C-heterocyclyl, aryl, R2 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(O)OR8, C(O)(1-3C-alkyl), NHC(O)(1-3C-alkyl), 2R11, NHC(O)NHR11 ,-S(O)n- 1-3C-alkyl, -S(O)2NR5R6 or a group selected from 1-3C-alkyl, 1-3C-alkoxy, 3- 6C-cycloalkyl, aryl, heteroaryl, -(1-3C-alkyl)-aryl, -(1-3C-alkyl)-heteroaryl, -O- (3-6C-cycloalkyl), -O-aryl, -O-(3-6C-heterocyclyl), -O-heteroaryl, -O-(1-3C- alkyl)-heteroaryl, -O-(1-3C-alkyl)-(3-6C-heterocyclyl), 3C-alkyl)-aryl, 2- 3C-alkenyl, lkynyl, wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from: hydroxy, halogen, lkyl, 1-3C-haloalkyl, 1-3C-alkoxy, -NR8R9, cyano, - C(O)NR8R9, -C(O)OR10, -NHC(O)R11, -NHC(O)NHR11, -NHS(O)2R11, 3- 6C-heterocyclyl, aryl, R3 is hydrogen, hydroxy, NR5R6, n, cyano, CO(NR8R9), C(O)OR8, C(O)(1-3C-alkyl), NHS(O)2R11, NHC(O)NHR11 , - S(O)n3C-alkyl, - S(O)2NR5R6 or a group selected from 1-3C-alkyl, 1-3C-alkoxy 3-6C- lkyl, aryl, heteroaryl, -(1-3C-alkyl)-aryl, -(1-3C-alkyl)-heteroaryl, -O-(3- loalkyl), -O-aryl, -O-(3-6C-heterocyclyl), -O-heteroaryl, -O-(1-3C-alkyl)- heteroaryl, -O-(1-3C-alkyl)-(3-6C-heterocyclyl), -O-(1-3C-alkyl)-aryl, NHC(O)(1-3C-alkyl), 2-3C-alkenyl, 2-3C-alkynyl, wherein said group being optionally substituted, one or more times, identically or ently, with a substituent selected from: hydroxy, halogen, lkyl, 1-3C-haloalkyl, lkoxy, -NR8R9, cyano, - C(O)NR8R9, -C(O)OR10, -NHC(O)R11, -NHC(O)NHR11, -NHS(O)2R11, 3- 6C-heterocyclyl, aryl, R4 is phenyl which is optionally substituted one, two or three times, identically or differently, with a halogen atom; R5 is hydrogen, 1-3C-alkyl, R6 is hydrogen, 1-3C-alkyl, R8 is hydrogen, lkyl which optionally is substituted with hydroxy, R9 is hydrogen, 1-3C-alkyl, R10 is hydrogen, 1-3C-alkyl, R11 is hydrogen, 1-3C-alkyl, X, Y is CH2; n is 0, 1, 2; or an e, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

Another aspect of the invention relates to compounds of formula (I), wherein R1 is hydrogen, hydroxy, NR5R6, CO(NR8R9), C(O)OR8, NHC(O)(1-6C-alkyl), or a group selected from lkyl, 1-3C-alkoxy, 3-6C-cycloalkyl, aryl, heteroaryl, wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from: halogen, 1-3C-alkyl, 1-3C-alkoxy, -C(O)OR10, 3cycloalkyl, 3-6C- cyclyl, aryl, R2 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(O)OR8, C(O)(1-3C-alkyl), NHC(O)(1-3C-alkyl), NHS(O)2R11, NHC(O)NHR11 ,-S(O)n- 1-3C-alkyl, -S(O)2NR5R6 or a group selected from 1-3C-alkyl, 1-3C-alkoxy, 3- 6C-cycloalkyl, aryl, heteroaryl, -(1-3C-alkyl)-aryl, -(1-3C-alkyl)-heteroaryl, -O- cycloalkyl), -O-aryl, 6C-heterocyclyl), -O-heteroaryl, -O-(1-3C- alkyl)-heteroaryl, -O-(1-3C-alkyl)-(3-6C-heterocyclyl), -O-(1-3C-alkyl)-aryl, 2- 3C-alkenyl, lkynyl, wherein said group being ally substituted, one or more times, identically or differently, with a substituent selected from: hydroxy, halogen, 1-3C-alkyl, 1-3C-haloalkyl, 1-3C-alkoxy, -NR8R9, cyano, - C(O)NR8R9, -C(O)OR10, )R11, -NHC(O)NHR11, -NHS(O)2R11, 3- 6C-heterocyclyl, aryl, R3 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(O)OR8, C(O)(1-3C-alkyl), NHS(O)2R11, NHC(O)NHR11 , - 1-3C-alkyl, - S(O)2NR5R6 or a group selected from 1-3C-alkyl, 1-3C-alkoxy 3-6C- lkyl, aryl, heteroaryl, -(1-3C-alkyl)-aryl, -(1-3C-alkyl)-heteroaryl, -O-(3- 6C-cycloalkyl), l, -O-(3-6C-heterocyclyl), -O-heteroaryl, 3C-alkyl)- heteroaryl, -O-(1-3C-alkyl)-(3-6C-heterocyclyl), -O-(1-3C-alkyl)-aryl, NHC(O)(1-3C-alkyl), 2-3C-alkenyl, 2-3C-alkynyl, wherein said group being optionally substituted, one or more times, identically or differently, with a substituent ed from: hydroxy, halogen, 1-3C-alkyl, 1-3C-haloalkyl, 1-3C-alkoxy, -NR8R9, cyano, - C(O)NR8R9, -C(O)OR10, -NHC(O)R11, -NHC(O)NHR11, -NHS(O)2R11, 3- 6C-heterocyclyl, aryl, R4 is phenyl which is optionally substituted one, two or three times, identically or differently, with a halogen atom; R5 is hydrogen, 1-3C-alkyl, R6 is hydrogen, 1-3C-alkyl, R8 is hydrogen, 1-3C-alkyl which optionally is substituted with hydroxy, R9 is hydrogen, 1-3C-alkyl, R10 is hydrogen, 1-3C-alkyl, R11 is hydrogen, 1-3C-alkyl, X, Y is CH2; n is 0, 1, 2; or an N-oxide, a salt, a tautomer or a isomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

A further aspect of the invention s to compounds of formula (I), wherein R1 is OR7; R2 is hydrogen, R3 is C(O)NR8R9, C(O)OR8, halogen, 1-6C-alkyl, 1-6C-alkoxy, R4 is phenyl which is ally substituted one, two or three times, identically or differently, with a halogen atom; R5 is en, 1-6C-alkyl, R6 is hydrogen, 1-6C-alkyl, R7 is 1-4C-haloalkyl, R8 is hydrogen, 1-6C-alkyl, R9 is hydrogen, 1-6C-alkyl, R10 is hydrogen, 1-6C-alkyl, R11 is hydrogen, 1-6C-alkyl, X, Y is CH2; n is 0, 1, 2; or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

A further aspect of the invention are compounds of formula (I), wherein R1 is hydrogen, lkoxy, R2 is hydrogen, R3 is C(O)NH2, C(O)OR8, halogen, 1-4C-alkyl, 1-4C-alkoxy, R4 is phenyl which is optionally substituted one, two or three times, identically or differently, with a halogen atom; R5 is hydrogen, 1-4C-alkyl, R6 is hydrogen, 1-4C-alkyl, R7 is 1-4C-haloalkyl, R8 is hydrogen, 1-4C-alkyl, R9 is hydrogen, 1-4C-alkyl, R10 is hydrogen, 1-4C-alkyl, R11 is en, 1-4C-alkyl, X, Y is CH2 n is 0, 1, 2; or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

Another aspect of the invention are compounds of formula (I) wherein R1 is hydrogen, methoxy, ethoxy, R2 is hydrogen, R3 is C(O)NH2, C(O)OR8, 1-3C-alkyl, bromine, methoxy, ethoxy, R4 is phenyl which is optionally substituted one, two or three times, identically or differently, with a halogen atom; R5 is hydrogen, lkyl, R6 is hydrogen, lkyl, R7 is aloalkyl, R8 is hydrogen, 1-4C-alkyl, R9 is hydrogen, 1-4C-alkyl, R10 is hydrogen, 1-4C-alkyl, R11 is hydrogen, 1-4C-alkyl, X, Y is CH2 n is 0, 1, 2; or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer A further aspect of the invention are compounds of formula (I) wherein R1 is hydrogen, 1-3C-alkoxy, R2 is hydrogen R3 is 1-3C-alkyl 1-3C-alkoxy, halogen, trifluoromethyl, C(O)NH2, COOR8, R4 is phenyl R8 is hydrogen, lkyl, X, Y is CH2 or an e, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

Another aspect of the invention are compounds of formula (I) wherein R1 is hydrogen, yl, amino, methoxy, ethoxy, butoxy, neyl, pyridine- 4-yl, pyrazolyl, 1-methyl-pyrazolyl, imidazoleyl, methyl, , -O-(CH2)-O- CH3, -O-CH2-phenyl, -O-CH2-cyclopropyl, -C(O)OCH3, -C(O)-NHCH3, -C(O)-NH2, 4- fluoro-phenyl, 2-C(O)OCH3, cyclopropyl, O)CH3, R2 is hydrogen, methyl, R3 is hydrogen, hydroxy, amino, methyl, ethyl, y, , -O-CH2- C(O)OCH3, -S-CH3, -SO2-CH3, bromine, chlorine, trifluoromethyl, C(O)NH2, COOH,C(O)OCH3, C(O)OCH2CH3, C(O)NH2, C(O)NHCH3, C(O)N(CH3)2, C(O)NH(CH2)2-OH, -CH=CH2, 4-fluoro-phenyl, NHC(O)CH3, NHC(O)CF3, NH-SO2- CH3, C(O)CH3, R4 is phenyl X, Y is CH2 or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

Another aspect of the invention are compounds of formula (I) wherein R1 is hydrogen, methoxy, R2 is hydrogen R3 is methyl, ethyl, methoxy, bromine, trifluoromethyl, C(O)NH2, COOH, C(O)OCH3, C(O)OCH2CH3, R4 is phenyl X, Y is CH2 or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or isomer.

In one aspect of the invention nds of formula (I) as bed above are selected from the group consisting of: 1-[4-(6-Methylphenylimidazo[1,2-b]pyridazinyl)phenyl]- cyclobutanamine 1-[4-(6-Ethylphenylimidazo[1,2-b]pyridazinyl)phenyl]- cyclobutanamine 1-{4-[3-Phenyl(trifluoromethyl)imidazo[1,2-b]pyridazin yl]phenyl}cyclobutanamine Ethyl 2-[4-(1-aminocyclobutyl)phenyl]phenylimidazo[1,2- b]pyridazinecarboxylate 2-[4-(1-Aminocyclobutyl)phenyl]phenylimidazo[1,2-b]- pyridazinecarboxamide 1-[4-(6-Methyloxyphenylimidazo[1,2-b]pyridazinyl)- phenyl]cyclobutanamine 1-[4-(6-bromomethyloxyphenylimidazo[1,2-b]pyridazin- 2-yl)phenyl]cyclobutanamine 2-[4-(1-aminocyclobutyl)phenyl]phenylimidazo[1,2-b]- pyridazinecarboxylic acid 1-[4-(6,8-dimethyloxyphenylimidazo[1,2-b]pyridazinyl)- phenyl]cyclobutanamine 2-[4-(1-aminocyclobutyl)phenyl]methoxyphenylimidazo [1,2-b]pyridazinecarboxamide 1-[4-(8-Methoxyphenylimidazo[1,2-b]pyridazinyl)- phenyl]cyclobutanamine Methyl 2-[4-(1-aminocyclobutyl)phenyl]methoxyphenylimidazo [1,2-b]pyridazinecarboxylate 1-[4-(6-Ethylmethoxyphenylimidazo[1,2-b]pyridazin yl)phenyl]cyclobutanamine 1-{4-[6-Methoxyphenyl(pyridinyl)imidazo[1,2-b]- zinyl]phenyl}cyclobutanami 1-{4-[6-Methoxyphenyl(1H-pyrazolyl)imidazo[1,2-b]- pyridazinyl]phenyl}cyclobutanamine HCl salt 1-[4-(6,8-Diethylphenylimidazo[1,2-b]pyridazinyl)- ]cyclobutanamine 1-[4-(6-Chlorophenylimidazo[1,2-b]pyridazinyl)phenyl]- utanamine 1-[4-(8-Methoxyphenylvinylimidazo[1,2-b]pyridazin yl)phenyl]cyclobutanamine 1-{4-[6-Chlorophenyl(1H-pyrazolyl)imidazo[1,2- b]pyridazinyl]phenyl}cyclobutanamine 3-Phenyl(1H-pyrazolyl)vinylimidazo[1,2- b]pyridazinyl]phenyl}cyclobutanamine 1-{4-[6-Ethylphenyl(1H-pyrazolyl)imidazo[1,2- b]pyridazinyl]phenyl}cyclobutanamine 2-[4-(1-Aminocyclobutyl)phenyl]ethoxy-N-methyl phenylimidazo[1,2-b]pyridazinecarboxamide 1-{4-[6-Chloro(1-methyl-1H-pyrazolyl) phenylimidazo[1,2-b]pyridazinyl]phenyl}cyclobutanamine 1-{4-[6-Chloro(1H-imidazolyl)phenylimidazo[1,2- b]pyridazinyl]phenyl}cyclobutanamine 1-[4-(3-Phenylimidazo[1,2-b]pyridazinyl)phenyl]- cyclobutanamine 2-[4-(1-Aminocyclobutyl)phenyl]methoxy-N-methyl phenylimidazo[1,2-b]pyridazinecarboxamide 1-{4-[3-Phenyl(1H-pyrazolyl)imidazo[1,2-b]pyridazin yl]phenyl}cyclobutanamine 2-[4-(1-Aminocyclobutyl)phenyl](2-methoxyethoxy) imidazo[1,2-b]pyridazinecarboxamide 1-{4-[8-(Benzyloxy)chlorophenylimidazo[1,2-b]- pyridazinyl]phenyl}cyclobutanamine 1-[4-(6-Chloroethoxyphenylimidazo[1,2-b]pyridazin yl)phenyl]cyclobutanamine Methyl 2-[4-(1-aminocyclobutyl)phenyl]phenylimidazo[1,2- b]pyridazinecarboxylate 1-Aminocyclobutyl)phenyl]phenylimidazo[1,2-b]- pyridazinol 1-{4-[6-(4-Fluorophenyl)phenylimidazo[1,2-b]pyridazin yl]phenyl}cyclobutanamine 2-[4-(1-Aminocyclobutyl)phenyl]phenylimidazo[1,2-b]- pyridazine-6,8-dicarboxamide 2-[4-(1-Aminocyclobutyl)phenyl]phenylimidazo[1,2-b]- pyridazinamine 1-{4-[6-(Methylsulfanyl)phenylimidazo[1,2-b]pyridazin yl]phenyl}cyclobutanamine N-{2-[4-(1-Aminocyclobutyl)phenyl]phenylimidazo[1,2-b]- pyridazinyl}acetamide N-{2-[4-(1{4-[6-(Methylsulfonyl)phenylimidazo[1,2-b]- pyridazinyl]phenyl}cyclobutanamine Methyl 1-aminocyclobutyl)phenyl]phenylimidazo[1,2- b]pyridazinecarboxylate N-{2-[4-(1-Aminocyclobutyl)phenyl]phenylimidazo[1,2-b]- pyridazinyl}-2,2,2-trifluoroacetamide 1-[4-(6-Bromophenylimidazo[1,2-b]pyridazinyl)phenyl]- cyclobutanamine 1-{4-[6,8-Bis(4-fluorophenyl)phenylimidazo[1,2-b]- pyridazinyl]phenyl}cyclobutanamine 1-{2-[4-(1-Aminocyclobutyl)phenyl]phenylimidazo[1,2-b]- pyridazinyl}ethanone 1-{4-[8-(4-Fluorophenyl)phenylimidazo[1,2-b]pyridazin yl]phenyl}cyclobutanamine N-{2-[4-(1-Aminocyclobutyl)phenyl]phenylimidazo[1,2-b]- pyridazinyl}methanesulfonamide 1-[4-(6-Chlorocyclopropylphenylimidazo[1,2-b]- pyridazinyl)phenyl]cyclobutanamine 1-[4-(3-Phenylpropylimidazo[1,2-b]pyridazinyl)phenyl]- cyclobutanamine 2-[4-(1-Aminocyclobutyl)phenyl]phenylimidazo[1,2-b]- pyridazinamine N-{2-[4-(1-Aminocyclobutyl)phenyl]phenylimidazo[1,2-b]- zinyl}acetamide 1-[4-(6-Chloro-7,8-dimethylphenylimidazo[1,2-b]pyridazin- 2-yl)phenyl]cyclobutanamine Methyl 2-[4-(1-aminocyclobutyl)phenyl]-7,8-dimethyl phenylimidazo[1,2-b]pyridazinecarboxylate 2-[4-(1-Aminocyclobutyl)phenyl]-7,8-dimethylphenylimidazo [1,2-b]pyridazinecarboxamide 1-[4-(6-Methoxy-7,8-dimethylphenylimidazo[1,2-b]- pyridazinyl)phenyl]cyclobutanamine 1-{4-[7,8-Dimethyl(methylsulfanyl)phenylimidazo[1,2-b]- pyridazinyl]phenyl}cyclobutanamine 1-[4-(6-Ethoxy-7,8-dimethylphenylimidazo[1,2-b]pyridazin- 2-yl)phenyl]cyclobutanamine Methyl 1-aminocyclobutyl)phenyl]phenyl(1H- pyrazolyl)imidazo[1,2-b]pyridazinecarboxylate Methyl 2-[4-(1-aminocyclobutyl)phenyl]ethoxyphenylimidazo [1,2-b]pyridazinecarboxylate Methyl 2-[4-(1-aminocyclobutyl)phenyl](1H-imidazolyl)- 3-phenylimidazo[1,2-b]pyridazinecarboxylate tert-Butyl {1-[4-(8-acetamidophenylimidazo[1,2-b]- pyridazinyl)phenyl]cyclobutyl}carbamate 2-[4-(1-Aminocyclobutyl)phenyl]phenyl(1H-pyrazol dazo[1,2-b]pyridazinecarboxamide 2-[4-(1-Aminocyclobutyl)phenyl]ethoxyphenylimidazo [1,2-b]pyridazinecarboxamide 2-[4-(1-Aminocyclobutyl)phenyl](1H-imidazolyl)-N- methylphenylimidazo[1,2-b]pyridazinecarboxamide 2-[4-(1-Aminocyclobutyl)phenyl]-N-methyl phenylimidazo[1,2-b]pyridazinecarboxamide 2-[4-(1-Aminocyclobutyl)phenyl](cyclopropylmethoxy)-N- methylphenylimidazo[1,2-b]pyridazinecarboxamide 2-[4-(1-Aminocyclobutyl)phenyl]-N-methylphenyl(1H- pyrazolyl)imidazo[1,2-b]pyridazinecarboxamide 1-Aminocyclobutyl)phenyl]-N-ethylphenylimidazo [1,2-b]pyridazinecarboxamide 2-[4-(1-Aminocyclobutyl)phenyl]phenyl(1H-pyrazol yl)imidazo[1,2-b]pyridazinecarboxylic acid 2-[4-(1-Aminocyclobutyl)phenyl]-N-methylphenylimidazo [1,2-b]pyridazinecarboxamide 1-Aminocyclobutyl)phenyl]-N,N-dimethylphenylimidazo [1,2-b]pyridazinecarboxamide 2-[4-(1-Aminocyclobutyl)phenyl]-N-(2-hydroxyethyl) phenylimidazo[1,2-b]pyridazinecarboxamide 2-[4-(1-Aminocyclobutyl)phenyl]-N-(2-hydroxyethyl) phenyl(1H-pyrazolyl)imidazo[1,2-b]pyridazine carboxamide Methyl 3-{2-[4-(1-aminocyclobutyl)phenyl]phenylimidazo [1,2-b]pyridazinyl}propanoate 1-{4-[6-Methoxyphenyl(1H-pyrazolyl)imidazo[1,2-b]- pyridazinyl]phenyl}cyclobutanamine 1-{4-[6-Methoxy(1-methyl-1H-pyrazolyl)phenylimidazo [1,2-b]pyridazinyl]phenyl}cyclobutanamine 1-{4-[6-Methoxyphenyl(pyridinyl)imidazo[1,2-b]- zinyl]phenyl}cyclobutanamine 6,8-Diethoxyphenylimidazo[1,2-b]pyridazinyl)- phenyl]cyclobutanamine 1-[4-(8-Butoxyethoxyphenylimidazo[1,2-b]pyridazin yl)phenyl]cyclobutanamine 1-[4-(6-Ethoxyphenylimidazo[1,2-b]pyridazinyl)- phenyl]cyclobutanamine 2-[4-(1-Aminocyclobutyl)phenyl]phenylimidazo[1,2-b]- pyridazinol Methyl ({2-[4-(1-aminocyclobutyl)phenyl]phenylimidazo- [1,2-b]pyridazinyl}oxy)acetate One aspect of the present invention are the compounds disclosed in the examples as well as the intermediates, especially a compound of general formula (II) shown below in scheme 1, as used for their synthesis. r aspect of the invention are compounds of formula (I), wherein R1 is hydrogen, hydroxy, NR5R6, CO(NR8R9), C(O)OR8, NHC(O)(1-6C-alkyl), or a group ed from 1-3C-alkyl, 1-3C-alkoxy, 3-6C-cycloalkyl, aryl, heteroaryl, wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from: halogen, 1-3C-alkyl, 1-3C-alkoxy, -C(O)OR10, 3cycloalkyl, 3-6C-heterocyclyl, aryl.

Another aspect of the invention are compounds of formula (I), wherein R1 is hydrogen, hydroxy, NR5R6, CO(NR8R9), C(O)OR8, NHC(O)(1-6C-alkyl), or a group selected from 1-3C-alkyl, 1-3C-alkoxy, ycloalkyl, heteroaryl, wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from: halogen, 1-3C-alkyl, 1-3C-alkoxy, -C(O)OR10, 3cycloalkyl, aryl.

Another aspect of the invention are compounds of formula (I), wherein R1 is en, hydroxy, NR5R6, CO(NR8R9), C(O)OR8, NHC(O)(1-6C-alkyl), or a group selected from 1-3C-alkyl, 1-3C-alkoxy, 3-6C-cycloalkyl, aryl, wherein said group being optionally substituted, one or more times, identically or differently, with a substituent ed from: halogen, 1-3C-alkyl, 1-3C-alkoxy, -C(O)OR10, 3cycloalkyl, 3-6C-heterocyclyl, aryl.

Another aspect of the invention are compounds of formula (I), wherein R1 is hydrogen, hydroxy, NR5R6, CO(NR8R9), C(O)OR8, NHC(O)(1-6C-alkyl), or a group selected from 1-3C-alkyl, 1-3C-alkoxy, 3-6C-cycloalkyl, wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from: halogen, 1-3C-alkyl, 1-3C-alkoxy, -C(O)OR10, 3cycloalkyl, 3-6C-heterocyclyl, aryl.

Another aspect of the invention are compounds of formula (I), n R1 is hydrogen, H(1-3C-alkyl), -C(O)NH2 or a group ed from 1-6C- alkoxy, heteroaryl which are optionally substituted with lkyl, 1-3C-alkoxy.

Another aspect of the invention are compounds of a (I), wherein R1 is lkoxy, preferably 1alkyoxy, especially methoxy.

Another aspect of the invention are compounds of formula (I), wherein R2 is hydrogen.

Another aspect of the ion are compounds of formula (I), wherein R3 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(O)OR8, C(O)(1-6C-alkyl), NHS(O)2R11, NHC(O)NHR11, - S(O)n6C-alkyl, -S(O)2NR5R6 or a group selected from 1-6C-alkyl, 1-6C-alkoxy ycloalkyl, aryl, heteroaryl, -(1- 6C-alkyl)-aryl, -(1-6C-alkyl)-heteroaryl, -O-(3-7C-cycloalkyl), -O-aryl, -O-(3-7C- heterocyclyl), -O-heteroaryl, -O-(1-6C-alkyl)-heteroaryl, -O-(1-6C-alkyl)-(3-7C- heterocyclyl), -O-(1-6C-alkyl)-aryl, NHC(O)(1-6C-alkyl), 2-6C-alkenyl, 2-6C-alkynyl, wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from: hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy, , cyano, - C(O)NR8R9, R10, -NHC(O)R11, -NHC(O)NHR11, -NHS(O)2R11, 3-7C- heterocyclyl, aryl.

Another aspect of the ion are compounds of formula (I), wherein R3 is hydrogen, y, NR5R6, halogen, cyano, CO(NR8R9), C(O)OR8, C(O)(1-3C-alkyl), NHS(O)2R11, NHR11 , - S(O)n3C-alkyl, -S(O)2NR5R6 or a group selected from 1-3C-alkyl, lkoxy 3-6C-cycloalkyl, aryl, heteroaryl, - (1-3C-alkyl)-aryl, -(1-3C-alkyl)-heteroaryl, -O-(3-6C-cycloalkyl), -O-aryl, -O-(3-6C- heterocyclyl), eroaryl, -O-(1-3C-alkyl)-heteroaryl, -O-(1-3C-alkyl)-(3-6C- heterocyclyl), -O-(1-3C-alkyl)-aryl, NHC(O)(1-3C-alkyl), 2-3C-alkenyl, 2-3C-alkynyl, wherein said group being optionally substituted, one or more times, identically or ently, with a substituent selected from: hydroxy, halogen, 1-3C-alkyl, 1-3C-haloalkyl, 1-3C-alkoxy, -NR8R9, cyano, - C(O)NR8R9, -C(O)OR10, -NHC(O)R11, -NHC(O)NHR11, -NHS(O)2R11, 3-6C- heterocyclyl, aryl.

Another aspect of the invention are compounds of a (I), wherein R3 is hydrogen, y, amino, bromine, methoxy, ethoxy, , pyridineyl, pyridineyl, pyrazolyl, 1-methyl-pyrazolyl, imidazoleyl, methyl, propyl, -O- (CH2)-O-CH3, -O-CH2-phenyl, -O-CH2-cyclopropyl, -C(O)OCH3, -C(O)-NHCH3, - C(O)-NH2, 4-fluoro-phenyl, -(CH2)2-C(O)OCH3, cyclopropyl, -NH-C(O)CH3, Another aspect of the invention are compounds of formula (I), wherein R3 is 1-4C-alkyl, COOR8, (CO)NH2, 1-4C-alkoxy, halogen, especially methyl, ethyl, trifluoromethyl, aminocarbonyl, methoxy,methoxycarbonyl, carbonyl, COOH, bromine. r aspect of the ion are compounds of formula (I), wherein R3 is NR8R9, -C(O)OR10, –C(O)NR8R9.

In another embodiment of the mentioned aspects, the invention relates to nds of formula (I), wherein R4 is an unsubstituted phenyl moiety.

Another aspect of the invention are compounds of a (I), wherein R8 is hydrogen, 1-4Calkyl, especially hydrogen or 1-2C-alkyl.

Another aspect of the ion are compounds of formula (I), wherein n is 0 or 2.

Another aspect of the invention are compounds of formula (I), wherein R1 is selected from the following groups: hydrogen, hydroxy, NR5R6, CO(NR8R9), C(O)OR8, NHC(O)(1-6C-alkyl), or a group selected from lkyl, 1-3C-alkoxy, 3-6C-cycloalkyl, aryl, heteroaryl, wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from: halogen, 1-3C-alkyl, 1-3C-alkoxy, -C(O)OR10, 3cycloalkyl, 3-6C-heterocyclyl, aryl R3 is selected from hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(O)OR8, C(O)(1-3C- alkyl), NHS(O)2R11, NHC(O)NHR11, - S(O)n3C-alkyl, -S(O)2NR5R6 or a group selected from lkyl, 1-3C-alkoxy 3-6C-cycloalkyl, aryl, heteroaryl, -(1-3C-alkyl)- aryl, -(1-3C-alkyl)-heteroaryl, -O-(3-6C-cycloalkyl), -O-aryl, 6C-heterocyclyl), - O-heteroaryl, 3C-alkyl)-heteroaryl, -O-(1-3C-alkyl)-(3-6C-heterocyclyl), -O-(1- 3C-alkyl)-aryl, NHC(O)(1-3C-alkyl), 2-3C-alkenyl, 2-3C-alkynyl, wherein said group being optionally tuted, one or more times, identically or ently, with a substituent selected from: hydroxy, halogen, 1-3C-alkyl, 1-3C-haloalkyl, 1-3C-alkoxy, -NR8R9, cyano, - 8R9, -C(O)OR10, -NHC(O)R11, -NHC(O)NHR11, -NHS(O)2R11, 3-6C- heterocyclyl, aryl. r aspect of the invention are compounds of formula (I), wherein R1 is selected from the following groups: is hydrogen, -C(O)NH(1-3C-alkyl), -C(O)NH2 or a group selected from 1-6C-alkoxy, heteroaryl which are optionally substituted with 1-3C-alkyl, 1-3C-alkoxy and R3 is – C(O)NR8R9.

Another aspect of the invention are compounds of formula (I), wherein R1 is selected from the ing groups: is en, -C(O)NH(1-3C-alkyl), -C(O)NH2 or a group selected from 1-6C-alkoxy, heteroaryl which are optionally substituted with 1-3C-alkyl, 1-3C-alkoxy and R3 is NR8R9.

Another aspect of the invention are compounds of formula (I), wherein R1 is selected from the following groups: is hydrogen, -C(O)NH(1-3C-alkyl), -C(O)NH2 or a group selected from 1-6C-alkoxy, heteroaryl which are ally tuted with 1-3C-alkyl, 1-3C-alkoxy and R3 is- C(O)OR10.

Another aspect of the invention are compounds of formula (I), n R1 is ed from the following groups: is hydrogen, -C(O)NH(1-3C-alkyl), -C(O)NH2 or a group selected from 1-6C-alkoxy, heteroaryl which are optionally substituted with 1-3C-alkyl, 1-3C-alkoxy and R3 is 1- 4C-alkyl, COOR8, (CO)NH2, 1-4C-alkoxy, halogen, especially methyl, ethyl, trifluoromethyl, aminocarbonyl, methoxy,methoxycarbonyl, carbonyl, COOH, bromine Another aspect of the invention is the use of a compound of formula (I) in the manufacture of a pharmaceutical composition for the treatment of a disease.

Particularly the e a benign or malignant neoplasia, more preferably breast cancer.

Another aspect of the ion is a pharmaceutical composition comprising a compound of formula (I) er with at least one pharmaceutically acceptable additive.

A still further aspect is a pharmaceutical composition comprising a compound of formula (I) and a second active ingredient, which is at least one further anti-cancer agent.

Definitions "1-6C-alkyl" is a straight-chain or branched alkyl group having 1 to 6 carbon atoms. es are methyl, ethyl, n propyl, iso-propyl, n butyl, iso-butyl, sec-butyl and tertbutyl , pentyl, hexyl, preferably 1-4 carbon atoms (1-4C-alkyl), more ably 1-3 carbon atoms (1-3C-alkyl). Other alkyl constituents mentioned herein having another number of carbon atoms shall be defined as mentioned above taking into account the different length of their chain. Whenever "alkyl" is part of a constituent consisting of "alkyl" together with r ent the definition of "alkyl" given above also applies.

The term alkenyl" is to be understood as preferably g a linear or branched, monovalent hydrocarbon group, which contains one or more double bonds, and which has 2, 3, 4, 5 or 6 carbon atoms, particularly 2 or 3 carbon atoms ("2-3C-alkenyl"), it being understood that in the case in which said alkenyl group contains more than one double bond, then said double bonds may be isolated from, or conjugated with, each other. Said alkenyl group is, for example, a vinyl, allyl, (E)- 2-methylvinyl, (Z)methylvinyl, homoallyl, (E)-butenyl, (Z)-butenyl, (E)-but enyl, (Z)-butenyl, -enyl, (E)-pentenyl, (Z)-pentenyl, (E)-pentenyl, (Z)-pentenyl, (E)-pentenyl, (Z)-pentenyl, hexenyl, (E)-hexenyl, (Z)-hex- 4-enyl, (E)-hexenyl, (Z)-hexenyl, (E)-hexenyl, (Z)-hexenyl, (E)-hexenyl, (Z)-hexenyl, isopropenyl, 2-methylpropenyl, 1-methylpropenyl, 2-methylprop- 1-enyl, (E)methylpropenyl, (Z)methylpropenyl, ylbutenyl, 2- methylbutenyl, 1-methylbutenyl, 3-methylbutenyl, (E)methylbutenyl, (Z)methylbutenyl, (E)methylbutenyl, (Z)methylbutenyl, (E) methylbutenyl, (Z)methylbutenyl, (E)methylbutenyl, methylbut enyl, (E)methylbutenyl, (Z)methylbutenyl, 1,1-dimethylpropenyl, 1- ethylpropenyl, 1-propylvinyl, 1-isopropylvinyl, 4-methylpentenyl, 3-methylpent- 4-enyl, 2-methylpentenyl, ylpentenyl, 4-methylpentenyl, (E) methylpentenyl, (Z)methylpentenyl, ( -m-ethy|pent3--enyl, ( methylpentenyl, ( E )- 1--methylpentenyl, (Z)- 1--m-ethy|pent3-enyl, ( E- pentenyl, (Z -m-ethy|pent-enyl,)- ( E -m-ethy|pent2--enyl,)- ( methylpentenyl, (E)-methylpentenyl, (Z)--methylpent-enyl, ( methylpentenyl, (Z)- 1--methylpentenyl, (E -m-ethy|pent 1--enyl, Z-4)- ( methylpentenyl, ( E methylpentenyl,)- (Z -methylpentenyl,)- ( methylpentenyl, (Z)methylpentenyl, (E)methylpentenyl, (Z)-1 - methylpentenyl, 3-ethylbutenyl, 2-ethylbutenyl, 1-ethylbutenyl, (E) utenyl, (Z)ethy|buteny|, (E)-2—ethy|buteny|, (Z)-2—ethylbut-2— enyl, ethylbutenyl, (Z)ethylbut-2—enyl, (E)ethylbutenyl, (Z) ethylbutenyl, 2-ethylbutenyl, (E)ethy|buteny|, (Z)ethy|buteny|, 2- propylpropenyl, 1-propylpropenyl, 2-isopropylpropenyl, 1-isopropylprop- 2-enyl, (E)-2—propylpropenyl, (Z)-2—propylpropenyl, (E)propylpropenyl, (Z)propylpropenyl, (E)-2—isopropylpropenyl, (Z)-2—isopropylpropenyl, (E)isopropylpropenyl, (Z)isopropylpropenyl, (E)-3,3-dimethylprop enyl, (Z)-3,3-dimethylpropenyl, 1-(1,1-dimethylethyl)ethenyl, buta-1,3-dienyl, penta-1,4-dienyl, hexa-1,5-dienyl, or methylhexadienyl group. Particularly, said group is vinyl or allyl.

The term "2—60-alkynyl" is to be tood as preferably meaning a linear or branched, lent hydrocarbon group which contains one or more triple bonds, and which contains 2, 3, 4, 5 or 6 carbon atoms, particularly 2 or 3 carbon atoms ("2—3C-alkynyl"). Said Cz-Ce-alkynyl group is, for example, ethynyl, -ynyl, propynyl, butynyl, butynyl, butynyl, pentynyl, pent ynyl, pentynyl, pentynyl, hexynyl, hex-2—inyl, hexinyl, hexynyl, hex- , 1-methylprop-2—ynyl, 2-methylbutynyl, 1-methylbutynyl, 1- methylbut-2—ynyl, 3-methylbutynyl, lpropynyl, 3-methylpentynyl, 2- methylpentynyl, 1-methylpentynyl, 2-methylpentynyl, 1-methylpent ynyl, 4-methylpentynyl, 1-methylpent-2—ynyl, 4-methylpentynyl, 3- methylpentynyl, 2-ethylbutynyl, 1-ethylbutynyl, 1-ethylbutynyl, 1- propylpropynyl, ropylpropynyl, 2,2-dimethylbutinyl, 1,1- dimethylbutynyl, 1,1-dimethylbut-2—ynyl, or 3,3-dimethylbutynyl group.

Particularly, said alkynyl group is ethynyl, propynyl, or prop-2—inyl.

NR5R6 represents "amino" as well as "mono- or C-alkylamino" radicals containing in addition to the nitrogen atom, independently one or two of the above mentioned 1-GC-alkyl radicals. es are the methyamino, the ethylamino, the isopropylamino, the dimethylamino, the diethylamino, the methy|(ethy|)amino and the diisopropylamino l The same is intended for any NRny residue mentioned within the claims or description.

"Aryl" represents a mono-, or bicyclic aromatic carbocyclic radical , as a rule, 6 to 10 carbon atoms; by way of example phenyl or naphthyl. Phenyl is preferred.

The term C-alkyI)-ary|" represents an aryl radical as defined above which is connected to the rest of the molecule via a straight or branched alkyl chain, preferably -aryl, or -(CH20H2)-aryl. Benzyl is particularly preferred.

The term "aryloxy" or "-O-aryl" represents the same aryl moieties as defined for the term aryl whereby the ring is connected via an oxygen atom to the rest of the molecule.

The term "-O-(1-6C-alkyI)-aryl" represents the same aryl moieties as defined for the term aryl whereby the ring is connected via a 6Ca|ky|) spacer to the rest of the molecule. Preferred —O-(1-6Ca|ky|) spacers in this context are —0- (CH2)-, or -O-(CH20H2)-. Benzyloxy is ularly red.

"Halogen" within the meaning of the present invention is iodine, bromine, chlorine or fluorine, preferably "halogen" within the meaning of the present ion is chlorine or fluorine, if halogen were used as a leaving group during synthesis bromine or iodine are preferred. "1-4C-Haloalkyl", which also can be defined as an alkyl moiety which is substituted one or more times with halogen, is a straight-chain or branched alkyl group having 1 to 4 carbon atoms in which at least one hydrogen is substituted by a halogen atom. Examples are chloromethyl or 2—bromoethyl. For a lly or tely fluorinated C1-C4-alkyl group, the following partially or completely fluorinated groups are consid-ered, for e: fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, 1,1-difluoroethyl, 1,2—difluoroethyl, 1,1,1- trifluoroethyl, tetrafluoroethyl, and penta-fluoroethyl, whereby fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, 1,1 -difluoroethyl, or 1,1 ,1- oroethyl are preferred. lly or completely fluorinated C1-C4-alkyl groups are considered to be encompassed by the term 1-4C-haloalkyl. "1 -6C-Alkoxy" represents radicals, which in addition to the oxygen atom, contain a straight-chain or bran-:ched alkyl radical having 1 to 6 carbon atoms.

Examples which may be mentioned are the hexoxy, pentoxy, , iso-ubutoxy, sec-butoxy, utoxy, pro-poxy, isopropoxy, ethoxy and methoxy radicals, preferred are methoxy, ethoxy, propoxy, isopropoxy. "3-7C-Cycloalkyl" stands for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, preferably cyclopropyl. "3-7C-Cycloalkyloxy" or -7C-cycloalkyl)" stands for cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy or cycloheptyloxy, preferably cyclopropyloxy.

The term "heteroaryl" represents a monocyclic 5- or 6—membered aromatic heterocycle sing without being restricted thereto, the 5-membered heteroaryl radicals furyl, thienyl, pyrrolyl, lyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl (1 ,2,4-triazolyl, 1,3,4-triazolyl or 1,2,3- lyl), thiadiazolyl (1 ,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl or 1,2,4-thiadiazolyl) and oxadiazolyl (1 ,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3- oxadiazolyl or 1 xadiazolyl), as well as the 6-membered heteroaryl radicals pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl, preferred 5— or 6-membered heteroaryl radicals are furanyl, thienyl, pyrrolyl, lyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl. More preferred 5- or 6—membered aryl ls are furanyl, thien-2—yl, pyrroIyl, thiazolyl, oxazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, nyl, pyridinyl, pyrimidin- 2—yl, pyrimidinyl, pyrazinyl or pyridazinyl.

The term "-(1-6C-a|ky|)-heteroary|" represents a heteroaryl radical as defined above which is connected to the rest of the molecule via a straight or ed alkyl chain, ably -(CH2)-heteroaryl, or -(CHzCH2)-heteroaryl, whereby - (CH2)-heteroaryl is particularly preferred.

The term "Heteroaryloxy" or "—O-heteroaryl" represents the same heteroaryl moieties as defined for the term heteroaryl whereby the ring is connected via an oxygen atom to the rest of the molecule.

The term "-O-(1-GC-alkyI)-heteroaryl" represents the same heteraryl moieties as defined for the term heteroaryl whereby the ring is connected via a —O-(1 - I) spacer to the rest of the molecule.

The term "—O-(1-GC-alkyl) spacer" can vary in the sense of the invention to have an alkylene chain having from 1-6, 1-5, 1-4, 1-3, 1-2 or 1 carbon atoms which can be straight or branched where possible. "3-7C-Heterocyclyl", or "heterocyclyl" represents a mono- or polycyclic, preferably mono- or bicyclic, more preferably monocyclic, nonaromatic heterocyclic radical containing, 4 to 10, preferably 4 to 7, ring atoms, and up to 3, preferably up to 2, hetero atoms and/or hetero groups from the series consisting of N, O, 8, 80, 802. The heterocyclyl radicals can be saturated or partially unsaturated and, unless stated otherwise, may be optionally substituted, one or more times, cally or differently, with a substituent selected from: 1-4C-alkyl, aloalkyl, 1-4C-alkoxy, hydroxy, fluorine, whereby the 1-4C-alkyl may be optionally further substituted with y.

Particularly preferred heterocyclic radicals are 4- to 7-membered monocyclic saturated cyclyl radicals having up to two hetero atoms from the series consisting of O, N and S. The following may be mentioned by way of example and by preference: yl, tetrahydrofuranyl, azetidinyl, 3-hydroxyazetidinyl, 3-fluoroazetidinyl, 3,3-difluoroazetidinyl, idinyl, 3-hydroxypyrrolidinyl, pyrrolinyl, piperidinyl, 3-hydroxypiperidinyl, 4-hydroxypiperidinyl, 3- fluoropiperidinyl, 3,3-difluoropiperidinyl, 4-fluoropiperidinyl, 4,4- difluoropiperidinyl, piperazinyl, N-methyl-piperazinyl, N-(2—hydroxyethyl)- piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, homopiperazinyl, N-methylhomopiperazinyl.

The term "heterocyclyloxy" or —O-heterocycly|" represents the same heterocyclic moieties as defined for the term heterocyclyl whereby a C atom in the ring is connected via an oxygen atom to the rest of the molecule. red heterocyclic moieties are either unsubstituted, or may be optionally substituted on a ring nitrogen arom with a substituent selected from: 1-4C-alkyl, 1-4C- haloalkyl, 1-4C-alkoxy.

The term "-O-(1-GC-alkyl)-heterocycly|" represents the same heterocyclyl moieties as defined for the term heterocyclyl whereby the ring is connected via a —O-(1-6Calkyl) spacer to the rest of the molecule. In one aspect of the invention heterocyclic moieties containing one or more ring nitrogen atom are preferably connected to the —O-(1alky|) spacer via one of the ring nitrogen atoms.

The term -(1-GC-alkyl)-heterocyclyl represents the same heterocyclyl moieties as d for the term heterocyclyl s.o. whereby the ring is connected via a -(1- GC-alkyl) spacer to the rest of the molecule.

The 1-6C-alkyl or the NH(CO)R11 group includes for example NH(CO)CH3, NH(CO)C2H5, NH(CO)C3H7, CH(CH3)2.

The NHS(O)2R11 group includes for example NHS(O)20H3, NHS(O)202H5, 2C3H7, NHS(O)2CH(CH3)2.

WO 36776 The NH(CO)NHR11 group includes for example NHC(O)NHCHB, NHC(O)NHC2H5.

The C(O)NR8R9 group includes, for example, C(O)NH2, C(O)N(H)CH3, C(O)N(CH3)2, C(O)N(H)CH2CH3, C(O)N(CH3)CHZCH3 or C(O)N(CHZCH3)2.

In the case of -NR8R9, when R8 and R9 together with the nitrogen atom to which they are attached form a 3-GC-heterocyclic ring, the term "3-6C- heterocyclic ring" is d above.

The C(O)OR8 group includes for example C(O)OH, C(O)OCHB, C(O)OC2H5, C(O)C3H7, C(O)CH(CH3)2, C(O)OC4H9, C(O)OC5H11, 6H13; for C(O)O(1-GCalkyl) the alkyl part may be straight or branched.

Constituents which are optionally substituted as stated herein, may be substi- tuted, unless otherwise noted, one or more times, independently from one another at any possible position. When any variable occurs more than one time in any constituent, each definition is ndent.

In case of R1, R2 or R3 it is understood that the groups selected from 1 alkyl, 1-6C-alkoxy, 3-7C-cycloalkyl, aryl, -(1-6C-alkyl)-aryl, -(1-6C-alkyl)- heteroaryl, -O-(3-7C-cyc|oa|ky|), -O-ary|, -O-(3-7C-heterocyc|y|), -O-heteroary|, - C-alkyI)-heteroaryl, GC-alkyl)-(3-7C-heterocyc|y|), -O-(1-GC-alkyl)- aryl may be optionally substituted, one or more times, identically or differently, with a substituent selected from: hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-GC-alkoxy, -NR8R9, cyano, -C(O)NR8R9, -C(O)OR10, -NHC(O)R11, - NHS(O)2R11. Preferably the groups -(1-6C-a|ky|)-ary|, -(1-6C-a|ky|)-heteroary|, - O-(1-GC-alkyI)-heteroaryl, GC-alkyl)-(3-7C-heterocyc|y|), -O-(1-GC-alkyl)- aryl.

The heteroarylic, or heterocyclic groups mentioned herein may be substituted by their given substituents or parent molecular , unless ise noted, at any possible position, such as e.g. at any substitutable ring carbon or ring nitrogen atom. Analogously it is being understood that it is possible for any heteroaryl or heterocyclyl group to be attached to the rest of the le via any suitable atom if chemically le. Unless otherwise noted, any heteroatom of a heteroarylic ring with unsatisfied valences mentioned herein is assumed to have the en atom(s) to satisfy the valences. Unless ise noted, rings containing nizable amino- or imino-type ring nitrogen atoms (-N=) may be preferably not quaternized on these amino- or imino-type ring nitrogen atoms by the mentioned substituents or parent molecular groups.

Salts of the compounds according to the invention include all inorganic and organic acid addition salts and salts with bases, especially a|| pharmaceutically acceptable inorganic and organic acid on salts and salts with bases, particularly a|| pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases customarily used in pharmacy.

One aspect of the invention are salts of the compounds according to the invention including all inorganic and organic acid addition salts, especially a|| pharmaceutically acceptable inorganic and organic acid addition salts, particularly a|| pharmaceutically acceptable inorganic and c acid addition salts customarily used in pharmacy. Another aspect of the ion are the salts with di- and tricarboxylic acids.

Examples of acid addition salts e, but are not limited to, hydrochlorides, hydrobromides, phosphates, es, sulfates, salts of sulfamic acid, formates, acetates, propionates, citrates, D-gluconates, benzoates, 2—(4-hydroxybenzoyl)- benzoates, butyrates, salicylates, sulfosalicylates, lactates, maleates, laurates, malates, fumarates, succinates, oxalates, malonates,pyruvates, acetoacetates, tartarates, stearates, benzensulfonates, toluenesulfonates, methanesulfonates, trif|uoromethansulfonates, 3-hydroxynaphthoates, benzenesulfonates, alinedisulfonates and trifluoroacetates.

Examples of salts with bases include, but are not limited to, lithium, sodium, ium, calcium, aluminum, magnesium, titanium, meglumine, ammonium, salts optionally derived from NH3 or organic amines having from 1 to 16 C- atoms such as e.g. ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N- methylmorpholine, arginine, lysine, ethylendiamine, N-methylpiperindine and and guanidinium salts.

The salts include insoluble and, ularly, water-soluble salts.

According to the person d in the art the compounds of formula (I) ing to this invention as well as their salts may n, e.g. when isolated in crystalline form, varying amounts of solvents. Included within the scope of the invention are therefore all solvates and in particular all hydrates of the compounds of formula (I) according to this ion as well as all solvates and in particular all hydrates of the salts of the compounds of formula (I) according to this invention.

The term "combination" in the present invention is used as known to persons skilled in the art and may be present as a fixed combination, a xed combination or kit-of-parts.

A "fixed combination" in the present invention is used as known to persons skilled in the art and is defined as a combination wherein the said first active ingredient and the said second active ient are t together in one unit dosage or in a single entity. One example of a "fixed combination" is a pharmaceutical composition wherein the said first active ingredient and the said second active ingredient are present in admixture for aneous administration, such as in a formulation. Another example of a "fixed combination" is a pharmaceutical combination wherein the said first active ingredient and the said second active ingredient are present in one unit without being in admixture.

A xed combination or "kit-of-parts" in the present invention is used as known to persons skilled in the art and is defined as a combination wherein the said first active ingredient and the said second active ingredient are present in more than one unit. One example of a non-fixed combination or kit-of-parts is a combination wherein the said first active ingredient and the said second active ingredient are present separately. The components of the xed combination or kit-of-parts may be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.

The term "(chemotherapeutic) ancer agents", includes but is not limited to (i) ting/carbamylating agents such as Cyclophosphamid (Endoxan®), lfosfamid (Holoxan®), Thiotepa (Thiotepa Lederle®), Melphalan (Alkeran®), or ethylnitrosourea (BCNU); (ii) platinum derivatives like cis-platin (Platinex® BMS), oxaliplatin (Eloxatin®), satraplatin or carboplatin (Cabroplat® BMS); (iii) antimitotic agents / tubulin tors such as vinca alkaloids (vincristine, vinblastine, vinorelbine), taxanes such as Paclitaxel (Taxol®), Docetaxel (Taxotere®) and analogs as well as new formulations and conjugates thereof (like the nanoparticle formulation Abraxane® with paclitaxel bound to albumin), lones such as Epothilone B (Patupilone®), Azaepothilone (lxabepilone®) or Sagopilone; (iv) topoisomerase inhibitors such as anthracyclines (exemplified by Doxorubicin / astin®), epipodophyllotoxines (examplified by Etoposide / Etopophos®) and camptothecin and camptothecin analogs (exemplified by lrinotecan / Camptosar® or Topotecan / Hycamtin®); (v) pyrimidine antagonists such as rouracil (5-FU), tabine (Xeloda®), Arabinosylcytosine / bin (Alexan®) or Gemcitabine (Gemzar®); (vi) purin antagonists such as 6—mercaptopurine (Puri-Nethol®), 6—thioguanine or fludarabine (Fludara®) and (vii) folic acid antagonists such as methotrexate trexat®) or premetrexed (Alimta®).

The term "target specific anti-cancer agent", includes but is not limited to (i) kinase inhibitors such as e.g. ib (Glivec®), ZD-1839 / Gefitinib a®), Bay43-9006 (Sorafenib, Nexavar®), SU11248 /Sunitinib (Sutent®), OSl-774/ Erlotinib va®), Dasatinib (Sprycel®), Lapatinib (Tykerb®), or, see also below, Vatalanib, Vandetanib (Zactima®) or Pazopanib; (ii) proteasome inhibitors such as PS-341 / Bortezumib (Velcade®); (iii) histone deacetylase inhibitors like SAHA (Zolinza®), PXD101, M8275, MGCD0103, eptide/ FK228, NVP-LBH589, Valproic acid (VPA), CRA/ PCI 24781, lTF2357, 88939 and butyrates (iv) heat shock protein 90 inhibitors like 17-allylaminogeldanamycin (17-AAG) or 17-dimethylaminogeldanamycin (17- DMAG); (v) vascular targeting agents (VTAs) like combretastin A4 phosphate or 2 / AC77OO and anti-angiogenic drugs like the VEGF antibodies, such as Bevacizumab (Avastin®), or KDR tyrosine kinase inhibitors such as PTK787/ ZK222584 (Vatalanib®) or Vandetanib ma®) or Pazopanib; (vi) monoclonal antibodies such as Trastuzumab (Herceptin®), Rituximab (MabThera/ Rituxan®), Alemtuzumab (Campath®), Tositumomab (Bexxar®), 0225/ Cetuximab (Erbitux®), Avastin (see above) or Panitumumab (Vectibix®) as well as mutants and conjugates of onal antibodies, e.g. Gemtuzumab ozogamicin (Mylotarg®) or lbritumomab tiuxetan (Zevalin®), and antibody fragments; (vii) oligonucleotide based therapeutics like 6-3139 / Oblimersen (Genasense®) or the DNMT1 tor M698; (viii) ike or / TLR 9 ts like Promune®, TLR 7 agonists like mod (Aldara®) or lsatoribine and analogues thereof, or TLR 7/8 agonists like Resiquimod as well as immunostimulatory RNA as TLR 7/8 agonists; (ix) protease inhibitors; (x) hormonal therapeutics such as anti-estrogens (e.g. Tamoxifen or Raloxifen), anti-androgens (e.g. Flutamide or x), LHRH analogs (e.g. Leuprolide, Goserelin or Triptorelin) and aromatase inhibitors (e.g. Femara, Arimedex or Aromasin).

Other "target specific anti-cancer agents" include bleomycin, ids such as all-trans retinoic acid (ATRA), DNA methyltransferase inhibitors such as 5-Aza- xycytidine (Decitabine, Dacogen®) and 5—azacytidine (Vidaza®), alanosine, cytokines such as interleukin-2, interferons such as interferon a2 or interferon-y, bcl2 antagonists (e.g. ABT-737 or analogs), death receptor agonists, such as TRAIL, DR4/5 agonistic antibodies, FasL and TNF-R agonists (e.g. TRAIL receptor agonists like mumab or lexatumumab).

Specific es of anti-cancer agents include, but are not d 131l-chTNT, ix, abiraterone, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, aminoglutethimide, amrubicin, amsacrine, anastrozole, arglabin, arsenic trioxide, asparaginase, azacitidine, ximab, BAY 80-6946, BAY 1000394, BAY 86-9766 (RDEA 119), can, bendamustine, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, buserelin, busulfan, cabazitaxel, calcium folinate, calcium levofolinate, capecitabine, carboplatin, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, cetuximab, chlorambucil, chlormadinone, chlormethine, tin, cladribine, clodronic acid, clofarabine, crisantaspase, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, deslorelin, dibrospidium chloride, docetaxel, uridine, bicin, bicin + estrone, eculizumab, edrecolomab, elliptinium acetate, eltrombopag, atin, enocitabine, epirubicin, epitiostanol, epoetin alfa, epoetin beta, eptaplatin, eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, fadrozole, filgrastim, fludarabine, fluorouracil, ide, formestane, fotemustine, fulvestrant, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, glutoxim, goserelin, histamine dihydrochloride, histrelin, hydroxycarbamide, l-125 seeds, ibandronic acid, ibritumomab tiuxetan, icin, ifosfamide, imatinib, imiquimod, improsulfan, interferon alfa, interferon beta, interferon gamma, ipilimumab, irinotecan, ixabepilone, lanreotide, lapatinib, lenalidomide, astim, lentinan, letrozole, leuprorelin, levamisole, lisuride, lobaplatin, lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melphalan, mepitiostane, mercaptopurine, methotrexate, methoxsalen, Methyl evulinate, methyltestosterone, mifamurtide, miltefosine, miriplatin, onitol, mitoguazone, ctol, mitomycin, mitotane, mitoxantrone, nedaplatin, nelarabine, nilotinib, nilutamide, nimotuzumab, nimustine, nitracrine, ofatumumab, omeprazole, oprelvekin, oxaliplatin, p53 gene therapy, paclitaxel, palifermin, palladium-103 seed, pamidronic acid, panitumumab, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pegfilgrastim, peginterferon alfa-2b, pemetrexed, pentazocine, pentostatin, peplomycin, perfosfamide, picibanil, pirarubicin, plerixafor, plicamycin, usam, polyestradiol phosphate, polysaccharide-K, er sodium, rexate, prednimustine, procarbazine, olide, -223 chloride, raloxifene, raltitrexed, ranimustine, razoxane, regorafenib, onic acid, rituximab, romidepsin, romiplostim, sargramostim, sipuleucel-T, sizofiran, sobuzoxane, sodium idazole, sorafenib, streptozocin, sunitinib, talaporfin, tamibarotene, tamoxifen, tasonermin, teceleukin, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, terone, tetrofosmin, thalidomide, thiotepa, thymalfasin, tioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, zumab, treosulfan, tretinoin, trilostane, triptorelin, trofosfamide, tryptophan, ubenimex, valrubicin, vandetanib, vapreotide, fenib, vinblastine, stine, vindesine, vinflunine, vinorelbine, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin.

A special aspect of the invention are combinations compsrising at least one compound according to claim 1 and at least one of the anti-cancer drugs selected from Ancestim, atrigel-leuprolide, axitinib, Bacillus Calmette-Guerin (BCG)-Tice, bosutinib, brentuximab vedotin, brivanib alaninate, Cervarix, cinacalcet hydrochloride, crizotinib, cytarabine ocfosfate, diethylstilbestrol, doxorubicin eluting beads, enzastaurin hydrochloride , etoposide phosphate um salt, floxuridine, fludeoxyglucose (18F), Gardasil, histrelin acetate, icotinib hydrochloride, ingenol mebutate, interferon alfa-2A, interferon alfa-2b interferon alfa-n1, interferon alfa interferon n1, ketoconazole, leucovorin / UFT, leuprolide acetate depot, yroxine sodium, liposomal cytarabine, liposomal daunorubicin, mal doxorubicin, M-Vax, MDV-3100, midostaurin, minocycline hydrochloride, motesanib diphosphate, nab- CD3, oblimersen sodium octreotide acetate, omacetaxine mepesuccinate, ombrabulin hydrochloride, paclitaxel nanoparticles, paclitaxel poliglumex, PEG- mal doxorubicin hydrochloride, pilocarpine hydrochloride, pixantrone e, rapamycin, ridaforolimus, ruboxistaurin mesilate hydrate, ruxolitinib phosphate, thyrotropin alfa, trimetrexate glucuronate, VAL-083, vesnarinone, vincristine TCS, Virulizin, zotarolimus, AZD-8055, BEZ-235, BGT-226, BKM- 120, CAL-101, , GDC-0980, GSK-2110183, GSK-2636771, OSl-027, perifosine, PF-O4691502, pictrelisib, PX-866, triciribine phosphate, UCN-OI, XL- 147, XL-765, 62, AS-703026, E-6201, selumetinib, trametinib yl sulfoxide.

The compounds according to the invention and their salts can exist in the form of tautomers which are included in the embodiments of the invention.

The compounds of the invention may, depending on their structure, exist in different stereoisomeric forms. These forms include configurational isomers or optionally conformational isomers iomers and/or reoisomers including those of somers). The present invention therefore includes enantiomers, diastereoisomers as well as mixtures thereof. From those mixtures of enantiomers and/or disastereoisomers pure stereoisomeric forms can be isolated with methods known in the art, ably methods of chromatography, especially high pressure liquid chromatography (HPLC) using achiral or chiral phase. The invention further includes all mixtures of the stereoisomers mentioned above independent of the ratio, including the racemates.

Some of the compounds and salts according to the invention may exist in ent crystalline forms (polymorphs) which are within the scope of the invention.

Furthermore, derivatives of the compounds of a (I) and the salts thereof which are ted into a compound of formula (I) or a salt thereof in a biological system (bioprecursors or pro-drugs) are covered by the invention.

Said biological system is e.g. a mammalian organism, ularly a human subject. The bioprecursor is, for example, converted into the nd of formula (I) or a salt thereof by metabolic processes.

The intermediates used for the synthesis of the compounds of claims 1-5 as described below, as well as their use for the synthesis of the compounds of claims 1-5, are one further aspect of the present ion. Preferred intermediates are the Intermediate Examples as disclosed below.

The compounds according to the invention can be prepared as follows.

The compounds according to the invention can be prepared according to the ing scheme, Scheme 1 : ‘x ‘x \ RX RX N, N, NH2 lRy .— Ry <— NC Hal Hal (VI) (VIII) (IX) MAR4 (VII) Y\X \x x RX R / / N "I h —> R o Y‘x (V) Ha| R4 N R4 (III) i R1 NH2 / \ N ("I R2 / wherein X, Y, R1, R2, R3 and R4 have the meanings defined above, whereby Rx Ry is R6, or a ting group,; Hal is halogen, preferably M is Mg-Hal, Zn- Hal, or Li.

WO 36776 Compounds of l formula (I) may be prepared from compounds of general formula (II). Rx may ally be R6, or a protecting group, or other such precursor which requires further manipulation.

The use of amine protecting groups in organic synthesis is well known to persons practiced in the art. Amine protecting groups include, but are not limited to: - carbamate protecting groups, including, but not d to methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate, (Fmoc), tertbuty | carbamate (BOC), allyl carbamate, and benzyl carbamate (082) including benzyl carbamates substituted on the phenyl ring, - amide ting groups, including, but not limited to N-formyl amide, and N-acetyl amide, - N-benzyl amine ting groups, including N-benzyl amines substituted on the phenyl ring.

When Rx and Ry of the compound of formula (I) are both hydrogen, Rx of the compound of formula (Il) may be a protecting group and Ry of the compound of formula (Il) may be hydrogen, the same protecting group as Rx, or a different protecting group, or Rx and Ry may combine to make a cyclic imide protecting group, such as an N-phthaloyl protecting group.

An amine protecting group may be reacted with a suitable reagent to remove the protecting group and replace it with a hydrogen. Such suitable reagents include, but are not limited to: - acid reagents, include, but are not limited to hydrochloric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, ic acid, boron tribromide; acid reagents may be used for the l of tert-butyl carbamate, N-formyl amide, or N-acetyl amide or ting groups. - base reagents, include, but are not limited to lithium ide, potassium hydroxide, sodium hydroxide, caesium carbonate, ammonium hydroxide; base reagents may be used for the removal of methyl carbamate, 9.fluorenyl ate, ethyl carbamate, N-formyl amide, or N-acetyl amide protecting groups. - nucleophilic reagents, e, but are not limited to lithium iodide, sodium iodide, potassium iodide, trimethylsilyl iodide, hydrazine, nucleophilic reagents may be used for the removal of benzyl carbamate, yl amide, N-acetyl amide, or N-phthaloyl ting groups. - metal-mediated reagents, including, but are not limited to nickel reagents, palladium reagents, platinum ts may be used for the removal of allyl carbamate protecting groups. - reduction reagents, include, but are not limited to sodium in ammonia, or the combination of a hydrogen source, such as, but not limited to hydrogen gas, formic acid, or a salt of formic acid and a metal reagent, including, but not limited to a nickel reagent, palladium reagent, platinum reagent; ion reagents may be used for the removal of 9- fluorenylmethyl carbamate, benzyl carbamate, or N-benzyl amine ting groups.

For example, Rx in compounds of general formula (Il) may be a protecting group such as the Boc group, —CO(OtBu). Preparation of compounds of general formula (I) may thus be accomplished by use of an appropriate deprotection reaction, such as in the case of a Boc group, acidic reaction conditions, for example, with a solution of 4M hydrochloric acid in dioxane or trifluoromethanesulfonic acid, in an appropriate solvent, such as for e DCM and methanol, at ambient ature. Further conditions to deprotect the Boc group, or further protecting groups that may be suitable for use in blocking the amino functionality in compounds of general formula (II), including their synthesis and deprotection, are found, for example, in T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, 1999, 3rd Ed., or in P.

Kocienski, Protecting Groups, Thieme Medical Publishers, 2000. Similarly, when Ry is not H, then Ry is a ting group, such as for example when Rx and Ry together form a cyclic protecting group such as for example a phthalamide.

Furthermore, compounds of l formula (Il) may contain functionality that may itself be r modified, thus ng introduction of the desired functionality in the R1, R2 or R3 groups. Such transformations include ions, reductions, philic substitutions, electrophilic substitutions, radical reactions, or metal promoted ons such as metal assisted cross- coupling reactions, such as for example Suzuki, Stille, or Heck reactions, or the like. Similarly, compounds of general formula (I) may also be modified in this way to provide further compounds according to the ion, providing the transformations do not cause unwanted side ons at the —NHR6 group.

Thus a further apect of the ion is a process for the manufacture of compounds of general formula (I) according to claim 1 by reacting a compound of general formula (II) (ll) wherein R1-R4 have the meaning as stated in claim 1 and Rx,Ry are R6, or a protecting group, wherein transformation to a compound of general formula (I) is lished by use of an appropriate deprotection reaction, whereby the protecting groups as discussed above can be used.

Another aspect of the invention is a process as disclosed above whereby subsequently of before the deprotection step, further modifications allowing introduction of the desired functionality in the R1, R2 or R3 groups can be performed. nds of general formula (Il) may be prepared from an intermediate ketone of general formula (III) and a heterocyclic amine of general formula (IV), by use of an appropriate cyc|isation reaction. For example, compounds of general formula (Il) may be prepared by reacting (Ill) and (IV) in an riate solvent, such as for example DMF or ethanol, at elevated temperatures from 50 0C to 150 oC. The use of basic additives such as a tertiary amine, for e triethylamine, may be beneficial.

Compounds of general formula (IV) are either commercially available, may be prepared using the s described in the es, may be ed using known methods, or may be prepared by analogous methods to those known by the person d in the art.

Compounds of general formula (III) may be prepared from a ketone of l formula (V) by use of an appropriate halogenation reaction. For example in the case of halogen is Br, a suitable bromination on, such as for example by reacting a ketone of general formula (V) with pyridinium hydrobromide perbromide in a suitable solvent, such as THF, at suitable temperatures, such as for example from O 0C to ambient temperature. nds of general formula (V) may be prepared from a compound of general formula (VI) using known methods, such as by addition of a suitable organometallic reagent (VII), in a le solvent, such as ethereal solvents, for example THF, at low temperatures, for example from -78 0C to -10 oC, preferably from -30 0C to -10 oC. Preferred organometallic reagents are for example organomagnesium reagents in which M is —MgC| or —MgBr, more preferably —MgC|.

Compounds of general formula (VI) may be prepared from compounds of general formula (VIII) using known methods, such as by way of a palladium catalysed cyanation reaction, using a suitable catalyst such as tetrakis(triphenylphosphine)pa||adium(O)[Pd(PPh3)4], a suitable cyano source, such as zinc dicyanide, a suitable solvent, such as DMF, whereby dry DMF may be beneficial, and elevated atures, such as up to the boiling point of the solvent, preferably at 80 oC.

Compounds of general formula (VIII) and (IX) are either commercially available, may be prepared using the methods described below, may be prepared using known methods, or may be prepared by ous methods to those known by the person skilled in the art.

One aspect of the invention are compounds of formula (II), especially wherein Rx is the Boc group, —CO(OtBu) and Ry is hydrogen.

Another aspect of the invention is the process for the manufacture of compounds of general formula (I), characterized in that a nd of formula (II) whereby R1 -R4, X and Y have the meaning according to claim 1 and RX is R6 or a ting group; Ry is hydrogen or a ting group, or Rx and Ry together, or Y and Rx together, may form a cyclic protecting group, Hal is halogen, is reacted with a solution of 4M hydrochloric acid in dioxane or trifluoromethanesulfonic acid, in an appropriate solvent, such as for example DCM and methanol, at ambient temperature forming a compound of formula (I) Thus another aspect of the invention is the use of intermediate of formula (II) for the preparation of compounds of formula (I).

One preferred aspect of the invention is the process for the preparation of the nds of claims 1-5 according to the Examples.

It is known to the person skilled in the art that, if there are a number of reactive centers on a starting or intermediate compound, it may be necessary to block one or more reactive centers temporarily by protective groups in order to allow a reaction to proceed specifically at the desired on center. A detailed description for the use of a large number of proven protective groups is found, for example, in T. W. Greene, tive Groups in Organic Synthesis, John Wiley & Sons, 1999, 3rd Ed., or in P. Kocienski, ting Groups, Thieme Medical Publishers, 2000.

The compounds according to the invention are isolated and purified in a manner known per se, e.g. by distilling off the solvent in vacuo and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary cation methods, such as tography on a suitable t material.

Furthermore, reverse phase preparative HPLC of compounds of the present invention which possess a sufficiently basic or acidic functionality, may result in the formation of a salt, such as, in the case of a compound of the present invention which is iently basic, a trifluoroacetate or formate salt for e, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example. Salts of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the persion skilled in the art, or be used as salts in subsequent biological assays. onally, the drying process during the isolation of compounds of the present invention may not fully remove traces of cosolvents, ally such as formic acid or trifluoroacetic acid, to give es or ion complexes. The person skilled in the art will recognise which so|vates or inclusion xes are acceptable to be used in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base, so|vate, inclusion complex) of a compound of the present invention as isolated as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.

Salts of the compounds of formula (I) ing to the invention can be obtained by dissolving the free compound in a suitable solvent (for example a ketone such as acetone, methylethylketone or methylisobutylketone, an ether such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol such as methanol, ethanol or isopropanol) which contains the desired acid or base, or to which the d acid or base is then added. The acid or base can be employed in salt preparation, depending on whether a mono- or polybasic acid or base is concerned and ing on which salt is desired, in an equimolar quantitative ratio or one differing therefrom. The salts are obtained by filtering, reprecipitating, precipitating with a non-solvent for the salt or by evaporating the solvent. Salts obtained can be converted into the free compounds which, in turn, can be converted into salts. In this manner, pharmaceutically unacceptable salts, which can be obtained, for example, as s products in the manufacturing on an industrial scale, can be converted into pharmaceutically acceptable salts by ses known to the person skilled in the art.

Pure reomers and pure enantiomers of the compounds and salts according to the invention can be obtained e.g. by asymmetric synthesis, by using chiral starting compounds in synthesis and by splitting up enantiomeric and diasteriomeric mixtures obtained in sis.

Enantiomeric and reomeric mixtures can be split up into the pure enantiomers and pure diastereomers by methods known to a person skilled in the art. Preferably, diastereomeric mixtures are separated by crystallization, in particular fractional crystallization, or chromatography. Enantiomeric mixtures can be separated e.g. by forming diastereomers with a chiral auxiliary agent, resolving the diastereomers obtained and removing the chiral auxiliary agent. As chiral ary agents, for e, chiral acids can be used to separate enantiomeric bases such as e.g. mandelic acid and chiral bases can be used to separate enantiomeric acids via formation of diastereomeric salts. Furthermore, diastereomeric derivatives such as diastereomeric esters can be formed from enantiomeric mixtures of alcohols or enantiomeric mixtures of acids, respectively, using chiral acids or chiral alcohols, respectively, as chiral auxiliary agents. Additionally, diastereomeric complexes or diastereomeric c|athrates may be used for separating enantiomeric mixtures. Alternatively, enantiomeric mixtures can be split up using chiral separating columns in chromatography.

Another le method for the ion of enantiomers is the enzymatic separation.

One preferred aspect of the invention is the s for the preparation of the compounds of claims 1-5 according to the examples.

Optionally, nds of the formula (I) can be converted into their salts, or, optionally, salts of the compounds of the formula (I) can be converted into the free compounds. Corresponding processes are customary for the skilled . ally, compounds of the a (I) can be converted into their N-oxides.

The N-oxide may also be introduced by way of an intermediate. N-oxides may be prepared by treating an appropriate precursor with an oxidizing agent, such as meta-chloroperbenzoic acid, in an appropriate solvent, such as dichloromethane, at suitable temperatures, such as from 0 °C to 40 °C, whereby room temperature is generally preferred. Further corresponding processes for forming N-oxides are customary for the d person.

Commercial utility The compounds of formula (I) and the stereoisomers of the compounds of formula (I) according to the invention are hereinafter referred to as the nds of the invention. In particular, the compounds of the ion are pharmaceutically acceptable. The compounds according to the invention have valuable pharmaceutical ties, which make them commercially utilizable. In ular, they inhibit the Pi3K/Akt pathway and exhibit cellular activity. They are expected to be commercially applicable in the y of diseases (e.g. diseases dependent on overactivated Pi3K/Akt). An abnormal activation of the PI3K/AKT pathway is an essential step towards the initiation and maintenance of human tumors and thus its inhibition, for example with AKT inhibitors, is understood to be a valid approach for treatment of human . For a recent review see Garcia-Echeverria et al (Oncogene, 2008, 27, 551-5526).

Cellular activity and analogous terms in the present invention is used as known to persons skilled in the art, as an e, inhibition of phosphorylation, tion of cellular proliferation, induction of apoptosis or chemosensitization.

Chemosensitization and analogous terms in the present invention is used as known to persons skilled in the art. These stimuli include, for example, effectors of death receptor and survival pathways as well as cytotoxic / chemotherapeutic and targeted agents and finally radiation therapy. Induction of apoptosis and analogous terms according to the present invention are used to identify a compound which excecutes mmed cell death in cells contacted with that compound or in combination with other compounds routinely used for therapy. sis in the present invention is used as known to persons skilled in the art.

Induction of apoptosis in cells contacted with the compound of this invention might not necessarily be coupled with tion of cell proliferation. Preferably, WO 36776 the inhibition of proliferation and/or induction of apoptosis are specific to cells with aberrant cell growth.

Furthermore, the compounds according to the present invention inhibit protein kinase activity in cells and tissues, causing a shift towards dephosphorylated substrate proteins and as functional consequence, for example the induction of apoptosis, cell cycle arrest and/or sensitization towards chemotherapeutic and target-specific cancer drugs. In a preferred embodiment, inhibition of the Pi3K/Akt pathway induces cellular effects as mentioned herein, alone, or in ation with standard cytotoxic or targeted anti-cancer drugs. nds according to the present invention exhibit roliferative and/or pro-apoptotic and/or chemosensitizing properties. Accordingly, the compounds of the present invention are useful for the treatment of hyperproliferative disorders, in particular cancer. Therefore the compounds of the present invention are useful to induce an anti-proliferative and/or pro-apoptotic and/or chemosensitizing effect in s, such as humans, suffering from a hyperproliferative disorders, like cancer.

The invention further s to a compound ing to the ion or a pharmaceutically acceptable salt thereof, for the treatment and/or prophylaxis, preferably treatment of (hyper)proliferative diseases and/or disorders sive to induction of apoptosis, which e benign neoplasia and malignant neoplasia, especially malignant neoplasia, including cancer and the tumor types as disclosed below.

Compounds ing to the present invention exhibit anti-proliferative and/or pro-apoptotic properties in mammals such as humans due to inhibition of metabolic activity of cancer cells which are able to survive despite of unfavourable growth conditions such as glucose depletion, hypoxia or other chemo stress.

WO 36776 Thus, the compounds according to the present invention are useful for treating, ameliorating or preventing diseases of benign or malignant behaviour as described herein, such as e.g. for inhibiting cellular neoplasia.

Neoplasia in the present invention is used as known to persons skilled in the art.

A benign neoplasia is described by roliferation of cells, incapable of forming an aggressive, asizing tumor in-vivo. In contrast, a malignant neoplasia is described by cells with multiple cellular and biochemical alities, e of forming a systemic disease, for example forming tumor metastasis in distant organs.

The compounds according to the present invention can be preferably used for the treatment of malignant neoplasia. Examples of malignant neoplasia treatable with the compounds according to the present invention include solid and hematological tumors. Solid tumors can be exemplified by tumors of the breast, bladder, bone, brain, central and peripheral nervous system, colon, endocrine glands (e.g. d and adrenal cortex), esophagus, endometrium, germ cells, head and neck, , liver, lung, larynx and hypopharynx, mesothelioma, ovary, as, prostate, rectum, renal, small intestine, soft tissue, testis, stomach, skin, ureter, vagina and vulva. ant sias include inherited cancers exemplified by Retinoblastoma and Wilms tumor. In addition, malignant neoplasias include primary tumors in said organs and corresponding ary tumors in distant organs ("tumor metastases").

Hematological tumors can be exemplified by aggressive and indolent forms of leukemia and lymphoma, namely non-Hodgkins disease, chronic and acute myeloid leukemia (CML/AML), acute lymphoblastic ia (ALL), Hodgkins disease, multiple myeloma and T-cell lymphoma. Also included are myelodysplastic syndrome, plasma cell neoplasia, paraneoplastic syndromes, and cancers of unknown y site as well as AIDS related malignancies.

In another aspect of the invention the compounds according to the present invention can be preferably used for the treatment of breast cancer.

It is noted that a malignant neoplasia does not necessarily e the formation of metastases in t organs. Certain tumors exert devastating s on the primary organ itself through their aggressive growth properties. These can lead to the destruction of the tissue and organ structure finally resulting in failure of the assigned organ function and death.

Drug ance is of particular importance for the frequent e of rd cancer eutics. This drug resistance is caused by various cellular and molecular mechanisms. One aspect of drug resistance is caused by constitutive activation of anti-apoptotic survival signals with PKB/Akt as a key signalling kinase. Inhibition of the Pi3K/Akt pathway leads to a resensitization towards standard chemotherapeutic or target specific cancer therapeutics. As a consequence, the commercial applicability of the compounds according to the present ion is not limited to 1St line treatment of cancer patients. In a preferred embodiment, cancer patients with ance to cancer herapeutics or target specific anti-cancer drugs are also amenable for treatment with these nds for e.g. 2nd or 3rd line treatment cycles. In particular, the compounds according to the present invention might be used in combination with standard chemotherapeutic or targeted drugs to resensitize tumors towards these agents.

Compounds according to the t invention are le for treatment, prevention or amelioration of the diseases of benign and malignant behavior as described above, such as e.g. benign or malignant neoplasia, particularly cancer, especially a cancer that is sensitive to Pi3K/Akt pathway inhibition.

The present invention further includes a method for treating, preventing or ameliorating diseases, preferably treating mammals, including humans, which are suffering from one of the abovementioned conditions, illnesses, disorders or diseases. The method is characterized in that a pharmacologically active and therapeutically effective and tolerable amount of one or more of the compounds ing to the present invention is administered to the subject in need of such treatment.

The t invention further includes a method for treating, ting or rating diseases responsive to inhibition of the Pi3K/Akt pathway, in a mammal, including human, preferably treating diseases responsive to inhibition of the Pi3K/Akt pathway, in a mammal, including human, comprising stering a pharmacologically active and therapeutically effective and tolerable amount of one or more of the compounds according to the present invention to said mammal.

The present invention further includes a method for ting protein kinase activity in cells comprising administering a pharmacologically active and therapeutically effective and tolerable amount of one or more of the compounds according to the present invention to a patient in need of such y.

The present invention further includes a method for treating roliferative diseases of benign or malignant behaviour and/or disorders responsive to induction of apoptosis, such as e.g. , particularly any of those cancer diseases described above, in a mammal, comprising administering a pharmacologically active and therapeutically effective and tolerable amount of one or more of the compounds according to the present invention to said mammal.

The present invention further includes a method for inhibiting cellular hyperproliferation or ing aberrant cell growth in a , comprising administering a pharmacologically active and therapeutically effective and tolerable amount of one or more of the compounds according to the present ion to said mammal.

The present invention further includes a method for inducing apoptosis in the therapy of benign or malignant neoplasia, particularly cancer, comprising administering a pharmacologically active and therapeutically effective and ble amount of one or more of the compounds according to the present invention to a subject in need of such therapy.

The present invention further includes a method for sensitizing towards chemotherapeutic or target-specific anti-cancer agents in a mammal, comprising administering a pharmacologically active and therapeutically effective and tolerable amount of one or more of the compounds according to the present ion to said mammal.

The present invention further includes a method for ng benign and/or malignant neoplasia, especially malignant neoplasia, particularly cancer, in a mammal, including human, sing administering a pharmacologically active and therapeutically ive and tolerable amount of one or more of the compounds according to the present invention to said mammal.

The present invention further includes a method for treating solid and hematological tumors, whereby solid tumors can be exemplified by tumors of the , bladder, bone, brain, central and peripheral nervous , colon, endocrine glands (e.g. thyroid and adrenal ), esophagus, endometrium, germ cells, head and neck, kidney, liver, lung, larynx and hypopharynx, elioma, ovary, pancreas, prostate, rectum, renal, small ine, soft tissue, testis, stomach, skin, ureter, vagina and vulva. Malignant neoplasias include inherited cancers exemplified by Retinoblastoma and Wilms tumor. In addition, malignant neoplasias include primary tumors in said organs and corresponding secondary tumors in distant organs ("tumor metastases"). and hematological tumors can be exemplified by aggressive and indolent forms of leukemia and lymphoma, namely non-Hodgkins disease, chronic and acute d leukemia (CML/AML), acute lymphoblastic leukemia (ALL), Hodgkins disease, le myeloma and T-cell lymphoma. Also included are myelodysplastic syndrome, plasma cell neoplasia, paraneoplastic syndromes, and cancers of n primary site as well as AIDS related malignancies.

A preferred aspect of the invention includes a method for treating breast cancer.

The present invention further relates to the use of the compounds for the pro- duction of pharmaceutical compositions, which are employed for the treatment, prophylaxis, and/or amelioration of one or more of the illnesses mentioned, preferably for the treatment of one or more of the illnesses mentioned.

The present invention further relates to the use of the compounds for the cture of pharmaceutical compositions for treating, preventing or ameliorating, preferably ng hyperproliferative diseases and/or disorders sive to the induction of apoptosis, such as e.g. beningn or malignant neoplasia, especially malignant neoplasia, in particular cancer, especially those cancer es and tumor types mentioned above.

The t ion further s to the use of the compounds according to this ion for the production of pharmaceutical compositions for treating, preventing or ameliorating, preferably treating benign or malignant neoplasia, especially malignant neoplasia, particularly cancer, such as e.g. any of those cancer diseases and tumor types described above.

The invention further relates to a compound according to the invention or a pharmaceutically acceptable salt f, for the treatment and/or prophylaxis, preferably treatment of (hyper)proliferative diseases and/or disorders sive to ion of apoptosis, which include benign neoplasia and malignant neoplasia, including cancer.

The invention further related to the use of a compound according to the invention or a pharmaceutically acceptable salt thereof, for the production of a pharmaceutical composition for the treatment, prevention or amelioration of a disease mediated by a dysregulated function of a single n kinase or multiple protein kinases and/or disorders responsive to the induction of apoptosis.

The invention further relates to a pharmaceutical ition, comprising a compound according to the invention or a pharmaceutically acceptable salt thereof, for the treatment and/or laxis, preferably treatment of (hyper)proliferative diseases and/or disorders responsive to induction of apoptosis, which include benign neoplasia and malignant sia, including cancer.

The t invention further s to the use of compounds and pharmaceutically acceptable salts according to the present ion for the manufacture of pharmaceutical compositions, which can be used for sensitizing towards chemotherapeutic and/or target specific anti-cancer agents.

The t invention further relates to the use of compounds according to the present invention for the manufacture of pharmaceutical compositions, which can be used for sensitizing towards radiation therapy of those es mentioned herein, particularly cancer.

The present invention further relates to the use of the nds according to the present invention for the manufacture of pharmaceutical compositions, which can be used in the treatment of diseases sensitive to protein kinase inhibitor therapy and different to cellular neoplasia. These non-malignant diseases include, but are not limited to benign prostate hyperplasia, neurofibromatosis, dermatoses, and myelodysplastic syndromes.

Methods of ng angiogenic disorders The present invention also provides methods of treating disorders and diseases associated with excessive and/or al angiogenesis. opriate and ectopic expression of angiogenesis can be deleterious to an organism. A number of pathological conditions are associated with the growth of extraneous blood vessels. These include, e.g., diabetic retinopathy, ischemic retinal-vein occlusion, and retinopathy of prematurity (Aiello et al. New Engl. J.

Med. 1994, 331, 1480; Peer et aI. Lab. Invest. 1995, 72, 638), age-related macular degeneration (AMD; see, Lopez et aI. Invest. Opththalmol. Vis. Sci. 1996, 37, 855), neovascular glaucoma, psoriasis, retrolental lasias, angiofibroma, inflammation, rheumatoid arthritis (RA), restenosis, in-stent restenosis, vascular graft restenosis, etc. In addition, the increased blood supply associated with cancerous and neoplastic tissue, encourages growth, leading to rapid tumor enlargement and metastasis. Moreover, the growth of new blood and lymph vessels in a tumor es an escape route for renegade cells, encouraging metastasis and the consequence spread of the cancer. Thus, nds of the present invention can be utilized to treat and/or prevent any of the entioned angiogenesis disorders, e.g., by inhibiting and/or reducing blood vessel formation; by inhibiting, blocking, reducing, decreasing, etc. endothelial cell proliferation or other types involved in angiogenesis, as well as causing cell death or apoptosis of such cell types.

The present invention further relates to pharmaceutical compositions comprising one or more of the compounds according to this invention and a ceutically acceptable carrier or diluent.

The present invention further relates to pharmaceutical itions comprising one or more of the compounds according to this invention and ceutically acceptable auxiliaries and/or excipients.

In the sense of the invention aries, vehicles, excipients, diluents, carriers or nts all mean additives which may be added to the compound to obtain a pharmaceutically acceptable composition suitable for stration.

Thus the invention relates to a pharmaceutical compositions comprising one or more of the compounds according to this invention and one or more pharmaceutically acceptable additives.

The pharmaceutical compositions ing to this invention are ed by processes, which are known per se and familiar to the person skilled in the art.

As pharmaceutical compositions, the compounds of the invention (= active com- pounds) are either employed as such, or preferably in combination with suitable pharmaceutical additives, e.g. in the form of tablets, coated tablets, dragees, pills, cachets, granules, capsules, s, suppositories, patches (e.g. as TTS), emulsions (such as e.g. micro-emulsions or lipid emulsions), suspensions (such as e.g. nano suspensions), gels, solubilisates or solutions (e.g. sterile solutions), or encapsuled in liposomes or as beta-cyclodextrine or yclodextrin derivative inclusion complexes or the like, the active compound t advantageously being between 0.1 and 95% and where, by the appropriate choice of the additives, a pharmaceutical administration form (e.g. a delayed release form or an enteric form) exactly suited to the active compound and/or to the desired onset of action can be achieved.

The person skilled in the art is familiar with auxiliaries, es, excipients, diluents, carriers or adjuvants which are suitable for the desired pharmaceutical formulations, preparations or compositions on account of r expert knowledge. In addition to solvents, gel formers, ointment bases and other active compound additives, for example antioxidants, dispersants, emulsifiers, preser- vatives, solubilizers (such as e.g. polyoxyethylenglyceroltriricinoleat 35, PEG 400, Tween 80, Captisol, Solutol H815 or the like), colorants, complexing agents, permeation promoters, stabilizers, s, binders, ners, egrating agents, buffers, pH regulators (e.g. to obtain l, alkaline or acidic formulations), polymers, lubricants, coating agents, propellants, tonicity adjusting agents, surfactants, flavorings, sweeteners or dyes, can be used.

In particular additives of a type appropriate to the desired formulation and the desired mode of administration are used.

The administration of the compounds, pharmaceutical compositions or combinations according to the invention may be performed in any of the generally accepted modes of stration available in the art. Illustrative examples of suitable modes of administration e intravenous, oral, nasal, parenteral, topical, transdermal and rectal delivery. Oral and intravenous deliveries are preferred.

Generally, the pharmaceutical compositions according to the invention can be administered such that the dose of the active compound is in the range customary for Pi3K/Akt pathway tors. In particular, a dose in the range of from 0.01 to 4000 mg of the active compound per day is preferred for an average adult patient having a body weight of 70 kg. In this respect, it is to be noted that the dose is dependent, for example, on the specific nd used, the species d, age, body weight, general health, sex and diet of the subject treated, mode and time of administration, rate of excretion, severity of the disease to be treated and drug combination.

The pharmaceutical composition can be administered in a single dose per day or in multiple subdoses, for example, 2 to 4 doses per day. A single dose unit of the pharmaceutical composition can contain e.g. from 0.01 mg to 4000 mg, preferably 0.1 mg to 2000 mg, more preferably 0.5 to 1500 mg, most preferably 1 to 500 mg, of the active compound. Furthermore, the pharmaceutical composition can be adapted to weekly, monthly or even more infrequent administration, for example by using an t, e.g. a subcutaneous or uscular t, by using the active compound in form of a sparingly soluble salt or by using the active compound coupled to a polymer.

The present invention r relates to combinations comprising one or more first active ingredients selected from the compounds of the invention and one or more second active ingredients selected from herapeutic anti-cancer agents and target-specific anti-cancer agents e.g. for treating, preventing or ameliorating diseases responsive or ive to inhibition of the Pi3K/Akt pathway, such as hyperproliferative diseases of benign or malignant behaviour and/or disorders responsive to the induction of apoptosis, more specifically benign or malignant hyperplasia, particularly , such as e.g. any of those cancer diseases described above, especially breast .

The invention further relates to the use of a pharmaceutical composition comprising one or more of the compounds according to this invention as sole active ient(s) and a pharmaceutically acceptable carrier or diluent in the manufacture of pharmaceutical products for the treatment and/or prophylaxis of the illnesses mentioned above.

The invention further relates to the use of a ceutical composition comprising one or more of the compounds according to this invention as sole active ingredient(s) and a pharmaceutically acceptable additives in the manufacture of pharmaceutical products for the treatment and/or prophylaxis of the illnesses ned above.

Depending upon the particular disease, to be treated or prevented, additional therapeutic active agents, which are normally administered to treat or prevent that disease, may optionally be coadministered with the compounds according to this invention. As used herein, additional therapeutic agents that are ly administered to treat or prevent a particular disease are known as appropriate for the disease being treated.

The anti-cancer agents mentioned herein above as combination partners of the compounds according to this invention are meant to include pharmaceutically acceptable derivatives thereof, such as e.g. their pharmaceutically able salts.

The person skilled in the art is aware of the total daily dosage(s) and administration form(s) of the additional therapeutic agent(s) nistered.

Said total daily dosage(s) can vary within a wide range depending from the agent combined. ln practising the present invention, the compounds according to this invention may be administered in combination therapy separately, sequentially, aneously, concurrently or chronologically staggered (such as e.g. as combined unit dosage forms, as separate unit dosage forms, as nt discrete unit dosage forms, as fixed or xed combinations, as -parts or as admixtures) with one or more standard therapeutics (chemotherapeutic and/or target specific anti-cancer agents), in particular art-known anti-cancer agents, such as any of e.g. those mentioned above.

In this context, the present invention further relates to a combination comprising a first active ingredient, which is at least one compound according to this invention, and a second active ingredient, which is at least one art-known anti- cancer agent, such as e.g. one or more of those mentioned herein above, for separate, tial, simultaneous, concurrent or chronologically staggered use in y, such as e.g. in therapy of any of those diseases mentioned herein.

The present invention further relates to a pharmaceutical ition comprising a first active ient, which is at least one compound according to this invention, and a second active ingredient, which is at least one own anti-cancer agent, such as e.g. one or more of those mentioned herein above, and, optionally, a pharmaceutically able carrier or diluent, for separate, sequential, simultaneous, concurrent or chronologically staggered use in therapy.

The present invention further relates to a combination product comprising a.) at least one compound according to this invention ated with a pharmaceutically acceptable carrier or diluent, and b.) at least one art-known anti-cancer agent, such as e.g. one or more of those mentioned herein above, formulated with a pharmaceutically acceptable carrier or diluent.

The present invention further relates to a kit-of-parts comprising a preparation of a first active ient, which is a compound according to this invention, and a pharmaceutically acceptable carrier or diluent; a ation of a second active ingredient, which is an art-known anti-cancer agent, such as one of those mentioned above, and a pharmaceutically acceptable carrier or diluent; for simultaneous, rent, sequential, separate or chronologically staggered use in therapy. Optionally, said kit comprises instructions for its use in therapy, e.g. to treat hyperproliferative diseases and diseases responsive or sensitive to inhibition of the Pi3K/Akt pathway, such as e.g. n or malignant neoplasia, particularly , more precisely, any of those cancer diseases described above.

The present invention further s to a combined preparation comprising at least one compound according to this invention and at least one art-known anti- cancer agent for simultaneous, concurrent, sequential or separate administration.

The present invention further relates to combinations, compositions, formulations, preparations or kits according to the present invention having Pi3K/Akt y inhibitory activity.

In on, the present invention further relates to a method for treating in combination therapy hyperproliferative diseases and/or disorders responsive to the induction of apoptosis, such as e.g. cancer, in a patient sing stering a ation, composition, formulation, preparation or kit as described herein to said patient in need thereof.

In addition, the present invention r relates to a method for treating hyperproliferative diseases of benign or malignant behaviour and/or disorders responsive to the induction of apoptosis, such as e.g. cancer, in a t comprising administering in combination therapy separately, simultaneously, concurrently, sequentially or chronologically staggered a pharmaceutically active and therapeutically effective and tolerable amount of a pharmaceutical composition, which comprises a compound according to this invention and a ceutically acceptable carrier or diluent, and a pharmaceutically active and therapeutically effective and tolerable amount of one or more art-known anti-cancer , such as e.g. one or more of those mentioned herein, to said patient in need thereof.

In further addition, the present invention relates to a method for treating, preventing or ameliorating hyperproliferative diseases and/or disorders 2012/056300 responsive to induction of apoptosis, such as e.g. benign or malignant neoplasia, e.g. cancer, particularly any of those cancer diseases mentioned herein, in a patient comprising administering separately, simultaneously, concurrently, tially or chronologically staggered to said t in need thereof an amount of a first active compound, which is a compound according to the present invention, and an amount of at least one second active compound, said at least one second active compound being a standard therapeutic agent, particularly at least one art-known anti-cancer agent, such as e.g. one or more of those chemotherapeutic and target-specific anti-cancer agents mentioned herein, wherein the amounts of the first active compound and said second active compound result in a therapeutic .

In yet further addition, the present invention relates to a method for treating, preventing or ameliorating, especially ng hyperproliferative diseases and/or disorders responsive to induction of apoptosis, such as e.g. benign or malignant neoplasia, especially malignanr neoplasia, e.g. cancer, particularly any of those cancer es and tumor types mentioned , in a patient comprising administering a combination according to the present invention.

In addition, the present invention further relates to the use of a composition, combination, formulation, preparation or kit according to this invention in the manufacture of a pharmaceutical product, such as e.g. a commercial package or a medicament, for treating, preventing or ameliorating, especially ng hyperproliferative diseases, and/or disorders responsive to the induction of apoptosis, such as e.g. malignant or benign neoplasia, especially malignant sia, such as e.g. cancer, particularly those diseases and tumor types mentioned herein,.

The present invention further relates to a commercial e comprising one or more compounds of the present ion together with instructions for simultaneous, concurrent, sequential or separate use with one or more chemotherapeutic and/or target specific anti-cancer agents, such as e.g. any of those mentioned herein.

The present invention further s to a commercial package consisting essentially of one or more compounds of the present invention as sole active ingredient together with instructions for simultaneous, concurrent, sequential or separate use with one or more chemotherapeutic and/or target specific anti- cancer agents, such as e.g. any of those mentioned herein.

The present invention further relates to a commercial package comprising one or more chemotherapeutic and/or target specific anti-cancer agents, such as e.g. any of those mentioned herein, together with instructions for simultaneous, concurrent, sequential or separate use with one or more nds according to the present invention.

The compositions, combinations, preparations, formulations, kits or packages mentioned in the t of the combination therapy according to this invention may also e more than one of the compounds according to this invention and/or more than one of the art-known anti-cancer agents mentioned.

The first and second active ingredient of a combination or kit-of-parts according to this invention may be provided as separate ations (i.e. independently of one another), which are subsequently brought together for simultaneous, rent, sequential, separate or chronologically staggered use in combination y; or packaged and presented together as separate components of a ation pack for simultaneous, concurrent, sequential, separate or chronologically staggered use in combination therapy.

The type of pharmaceutical formulation of the first and second active ingredient of a combination or kit-of-parts according to this invention can be ing, i.e. both ients are formulated in separate tablets or capsules, or can be different, i.e. suited for different stration forms, such as e.g. one active ingredient is formulated as tablet or capsule and the other is formulated for e.g. intravenous administration.

The amounts of the first and second active ingredients of the combinations, compositions or kits according to this invention may er comprise a therapeutically ive amount for the treatment, prophylaxis or amelioration of a hyperproliferative diseases and/or a disorder responsive to the induction of apoptosis, particularly one of those diseases mentioned herein, such as e.g. malignant or benign neoplasia, especially malignant neoplasia, e.g. cancer, like any of those cancer diseases and tumor types mentioned herein.

In on, compounds according to the present invention can be used in the pre- or post-surgical treatment of cancer.

In further addition, compounds of the present invention can be used in combination with radiation therapy.

As will be appreciated by persons skilled in the art, the invention is not limited to the particular embodiments described herein, but covers all modifications of said embodiments that are within the spirit and scope of the invention as defined by the appended claims.

The following examples illustrate the invention in greater detail, without cting it. r nds according to the ion, of which the preparation is not explicitly described, can be prepared in an ous way.

The compounds, which are mentioned in the examples and the salts thereof represent preferred embodiments of the invention as well as a claim covering all subcombinations of the residues of the compound of formula (I) as disclosed by the specific examples.

The term "according to" within the experimental section is used in the sense that the procedure ed to is to be used "analogously to".

Experimental part The following table lists the abbreviations used in this paragraph and in the Intermediate Examples and Examples section as far as they are not explained within the text body. NMR peak forms are stated as they appear in the spectra, possible higher order s have not been considered. Chemical names were generated using ACD/Name Batch version 12.01 or using AutoNom2000 as implemented in MDL ISIS Draw. In some cases lly ed names of commercially available reagents were used in place of AutoNom2000 generated names.

Abbreviation Meaning anh anhydrous boc t-Butoxycarbonyl CI chemical ionisation d doublet dd doublet of doublet DAD diode array detector DCM dichloromethane EtOAc ethyl acetate Eq. equivalent ESI electrospray (ES) ionization HPLC high performance liquid chromatography m multiplet MeOH methanol MPLC medium mance liquid tography MS mass spectrometry NMR nuclear magnetic resonance spectroscopy : chemical shifts (6) are given in ppm. The chemical shifts were corrected by setting the DMSO signal to 2.50 ppm using unless otherwise stated.

PYBOP (benzotriazolyloxy)tripyrrolidinophosphium hexafluorophosphate q quartet l‘.t. 01‘ 11 room temperature RT retention time (as measured either with HPLC or UPLC) in minutes s singlet t triplet THF ydrofuran UPLC ultra performance liquid chromatography Other abbreviations have their meanings customary per se to the skilled person.

The various aspects of the invention described in this application are illustrated by the following examples which are not meant to limit the invention in any way.

Examples S rd Procedures Analytical S was performed using UPLC-MS Method 1 unless otherwise stated. The masses (m/z) are ed from the positive mode electrospray ionisation unless the negative mode is indicated (ES-).

Method 1: ment: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEH C18 1.7 50x2.1mm; eluent A: water + 0.1% formic acid, eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60 °C; injection: 2 ul; DAD scan: 210-400 nm; ELSD Method 2: Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEH C18 1.7 50x2.1mm; eluent A: water + 0.2% ammonia, Eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 ml/min; ature: 60 °C; injection: 2 ul; DAD scan: 210-400 nm; ELSD Method 3: Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEH C18 1.7 mm; eluent A: water + 0.1% ammonia, eluent b: acetonitrile; gradient: 0-1.6 min 1-99% B, 0 min 99% B; flow 0.8 ml/min; temperature: 60 °C; ion: 2 ul; DAD scan: 210-400 nm; ELSD Method 4: instrument: Waters Acquity UPLC-MS SQD 3001 ; column: Acquity UPLC BEH C18 1.7 50x21 mm; eluent A: water + 0.2% ammonia, eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60 °C; injection: 2 ul; DAD scan: 210-400 nm; ELSD Intermediate Examples Intermediate e Int-1: tert-Butyl {1 -[4-(6-methylphenylimidazo[1 ,2-b]pyridazinyl)phenyl]- cyclobutyl}carbamate o ,1 N o/1\CH3 H CH3 / I Step 1: tert-Butyl [1-(4-bromophenyl)cyclobutyl]carbamate The free base of commercially available 1-(4-bromopheny|)cyc|obutanamine hydrochloride [CAS 1 1933890] (8.99 g, 34.24 mmol, 1.0 eq) was prepared as s: (8.99 g, 34.24 mmol, 1,0 eq) of the hydrochloride salt was taken up in DCM and washed sequentially with aqueous sodium bicarbonate and water and the organic portion was tried and concentrated.

The crude amine was taken up in dry THF (120 mL) and diisopropylethylamine (17.62 mL, 102.7 mmol, 3.0 eq) under nitrogen and a solution of di-tert- butyldicarbonate (8.22 g, 37.6 mmol, 1.1 eq) in THF (20 mL) was added. The reaction was d at rt overnight. The mixture was partitioned between EtOAc and water and the extracted organic phase was washed with brine and concentrated in vacuo to give the title nd.

Alternatively, the title compound may be prepared by known methods, such as those given in WO2008/70041, in particular from commercially ble (4- bromophenyl)acetonitrile.

Step 2: tert-Butyl [1-(4-cyanophenyl)cyclobutyl]carbamate The title compound may be prepared from by known s, such as those given in WO2008/70041, in particular from tert-butyl [1-(4- bromopheny|)cyc|obuty|]carbamate.

Alternatively, tert-butyl [1-(4-cyanopheny|)cyc|obuty|]carbamate (CAS 1032349- 97-5) may be obtained commercially.

Step 3: tert-Butyl {1-[4-(phenylacetyl)phenyl]cyclobutyl}carbamate The title compound may be prepared by known s, such as those given in W02008/70041, in particular from tert-butyl [1-(4- cyanophenyl)cyclobutyl]carbamate.

Step 4: tert-Butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate [Int-1 A] . 0 CH3 GO O CH H CH3 3 A mixture of utyl {1 -[4-(phenylacetyl)phenyl]cyclobutyl}carbamate (5.0 g, 13.68 mmol, 1.0 eq) and nium hydrobromide perbromide (4.38 g, 13.68 mmol, 1.0 eq) in THF (78 mL) was stirred at 0 °C for 30 minutes. The mixture was partitioned between EtOAc and water and the organic phase washed respectively with aqueous sodium thiosulfate solution and brine, dried, filtered through a silicone coated filter paper and concentrated in vacuo to give the crude title compound (5.44 g, 93% purity by UPLC-MS) which was used without further purification.

S (Method 4): RT = 1.49 min; m/z = 442.21 (ES-, M-H, M = C23H267QBI'N03).

Step 5: tert-Butyl {1-[4-(6-methylphenylimidazo[1,2-b]pyridazinyl)- phenyl]cyclobutyl}carbamate [Int-1] A mixture of crude tert-butyl((1-{ [bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example lntA (1.00 g, ~80% purity, 1.87 mmol, 1.0 eq), 6-methylpyridazinamine (CAS—Nr. 18591- 82-7, 0.245 g, 2.24 mmol, 1.2 eq), N,N-diisopropylethylamine (0.33 mL, 1.87 mmol, 1.0 eq) and activated 3A molecular sieves in panol (5.7 mL) was heated for 7 hours under reflux. On cooling, the e was partitioned between DCM and water, stirred vigorously and filtered through a silicone coated filter paper. The filtrate was trated in vacuo. UPLC analysis of the crude product ted a purity of >90%. The crude product was used in the next step without further purification.

UPLC-MS (Method 1): RT = 1.41 min; m/z = 455.89 (M+H).

Intermediate Example Int-2: tert-Butyl {1 -[4-(6-ethylphenylimidazo[1 ,2-b]pyridazinyl)- phenyl]cyclobutyl}carbamate 2012/056300 A e of crude tert-butyl (1 -{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)- carbamate that was prepared in a manner analgous to that described for Intermediate Example IntA (1.85 g, ~80% purity, 3.45 mmol, 1.0 eq), 6- yridazinammonium chloride (CAS—Nr. 11785856, 0.660 g, 4.14 mmol, 1.2 eq), isopropylethylamine (1.20 mL, 6.89 mmol, 2.0 eq) and activated 3A molecular sieves in isopropanol (10.5 mL) was heated for 12 hours under reflux. On cooling, the mixture was partitioned between DCM and water, stirred vigorously and filtered through a silicone coated filter paper. The filtrate was trated in vacuo. The crude mixture was ed via MPLC (Biotage lsolera; 100 g SNAP cartridge: hexane -> hexane/ethyl acetate 2/1) to give 700 mg (43% yield) of the title compound in 69% purity (UPLC).

UPLC-MS (Method 3): RT = 1.53 min; m/z = 469.34 (M+H).

Intermediate Example Int-3: tert-Butyl (1 -{4-[3-phenyl(trif|uoromethyl)imidazo[1 ,2-b]pyridazinyl]- phenyl}cyclobutyl)carbamate H CI?"3 A mixture of crude tert-butyl (1 -{4- [bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example IntA (1.85 g, ~80% , 3.45 mmol, 1.0 eq), 6-(trifluoromethyl)pyridazinamine (CAS-Nr. 9357775, 0.674 g, 4.14 mmol, 1.2 eq), N,N-diisopropylethylamine (0.60 mL, 6.89 mmol, 1.0 eq) and activated 3A molecular sieves in isopropanol (10.5 mL) was heated for 7 hours under reflux. On cooling, the e was partitioned between DCM and water, stirred vigorously and filtered through a silicone coated filter paper. The filtrate was concentrated in vacuo. The crude mixture was ed via MPLC (Biotage lsolera; 100 g SNAP cartridge: hexane -> hexane/ethyl acetate 2/1) to give 680 mg (34% yield) of the title compound.

UPLC-MS (Method 3): RT = 1.56 min; m/z = 509.29 (M+H).

Intermediate Example Int-4: Ethyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)—3- phenylimidazo[1,2-b]pyridazine—6-carboxylate 91.1"; H CH3 HSCJ A mixture of crude tert-butyl (1 -{4- [bromo(phenyl)acetyl]pheny|}cyclobuty|)carbamate that was prepared in a manner us to that described for Intermediate Example lntA (3.3 g, ~80% purity, 5.79 mmol), ethyl 6-aminopyridazinecarboxylate (CAS-Nr. 985487, 1 g, 5.57 mmol), N,N-diisopropylethylamine (0.97 mL, 5.57 mmol) and activated 3A molecular sieves in isopropanol (30.4 mL) was heated for 20 hours under reflux. On g the mixture was partitioned n DCM and water, stirred vigorously and filtered through a silicone coated filter paper. The filtrate was trated in vacuo, taken up in DCM and washed with dilute aqueous hydrochloric acid (1 N) and brine, dried and concentrated in vacuo to give the crude title compound. Purification was achieved by chromatography on silica (gradient elution: Hexane:EtOAc 9:1 to Hexane:EtOAc 1:1) to give the title compound (2.80 g, 92% purity, 90% .

UPLC-MS (Method 3): RT = 1.51 min; m/z = 513.41 (M+H). 1H-NMR (400 MHz, d6-DMSO): 6 = 8.29 (d, 1H), 7.74 (d, 1H), 7.50 - 7.56 (m, 8H), 7.31 (d, 2H), 4.33 (q, 2H), 2.28 - 2.39 (m, 4H), 1.88 - 1.99 (m, 1H), 1.68 - 1.80 (m, 1H), 1.26 - 1.29 (m, 9H), 1.08 (br s, 3H).

Intermediate Example Int-5: tert-Butyl (1 -{4-[3-phenylmethoxyimidazo[1 ,2-b]pyridazin-2—yl]- phenyl}cyclobutyl)carbamate JLo I.) I2 CH3 A mixture of crude tert-buty|((1-{ [bromo(phenyl)acetyl]pheny|}cyc|obutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example IntA (0.67 g, 1.50 mmol), omethoxypyridazine (CAS Registry No. 72528, 0.23 g, 1.80 mmol, 1.2 eq), N,N-diisopropylethylamine (0.74 mL, 1.50 mmol, 1.0 eq) and powdered activated 3A molecular sieves (10 g) in isopropanol (78 mL) was heated at the reflux temperature for 8 h. On cooling, the mixture was ed through a pad of Celite. The Celite was washed with DCM, and the combined organics were washed with water, dried with sodium sulfate and concentrated under reduced pressure to give utyl (1-{4-[3-phenyImethoxyimidazo[1,2- b]pyridaziny|]pheny|}cyc|obuty|)carbamate (0.55 g, 78% yield).

UPLC-MS (Method 3): RT = 1.52 min; m/z (rel intensity) 471 (95, ), 943 (100, 2M+H)+); ES— m/z (rel intensity) 469 (20, (M-H)'). 1H-NMR (d6—DMSO): 6 100-120 (br s, 3H), 1.20-1.37 (br s, 6H), .81 br s, 1H), 1.85-2.00 (m, 1H), 2.25-2.38 m, 4H), 3.80 (s, 3H), 6.92 (d, J=9.6 Hz, 1H), 7.28 (d, J=8.5 Hz, 2H), 7.37-7.59 (m, 8H), 8.50 (d, J=9.6 H, 1H).

Intermediate Example Int-6: tert-Butyl (1 -{4-[3-phenyl-6,8-dibromoimidazo[1 ,2-b]pyridazinyl]- phenyl}cyclobutyl)carbamate A mixture of crude tert-buty|((1-{ [bromo(phenyl)acetyl]pheny|}cyc|obutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example IntA (5.80 g, 13.1 mmol), 3-amino-4,6-dibromopyridazine (CAS Registry No. 12064875, 3.96 g, 15.7 mmol, 1.2 eq), N,N-diisopropylethylamine (2.3 mL, 13.0 mmol, 1.0 eq) and powdered activated 3A molecular sieves (10 g) in isopropanol (70 mL) was heated at the reflux ature for 8 h. On cooling, the mixture was filtered through a pad of Celite. The Celite was washed with DCM, and the combined organics were washed with water, dried with sodium sulfate and concentrated under reduced re. The remaining material was purified using MPLC ge a; 100 g SNAP cartridge: 100% hexane 2.0 min., gradient to 75% hexane /25% EtOAc 2.5 min., 75% hexane /25% EtOAc 4.5 min., gradient to 50% hexane /50% EtOAc 2 min., 50% hexane /50% EtOAc 4.5 min., gradient to 100% EtOAc 2.5 min., 100% EtOAc 5.7 min.) to give partially purified tert-butyl (1 -{4-[3-phenyI-6,8-dibromoimidazo[1 ,2-b]pyridazin ny|}cyc|obutyl)carbamate (2.65 g, ~82% pure, 28% yield): UPLC-MS (Method 3): RT = 1.67 min; m/z (rel intensity) 597 (50, (M+H)+). 1H-NMR (d6-DMSO): 0 1.00120 (br s, 3H), 1.20-1.37 (br s, 6H), 1.65-1.81 (m 1H), 1.85-2.00 (m, 1H), 2.25-2.38 m, 4H), 3.80 (s, 3H), 6.92 (d, J=9.6 Hz, 1H), 7.28 (d, J=8.5 Hz, 2H), 7.37-7.59 (m, 8H), 8.50 (d, J=9.6 Hz, 1H).

The following examples were prepared in a manner analogous to Intermediate Example Int-6 by ng the appropriate amine with utyl (1 -{4- [bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate [prepared in a manner analgous to that described for Intermediate Example Int-1A] Intermediate Structure/ Name Characterization Example 1 UPLC-MS (Method 3): RT = 1.65 min; m/z (rel intensity) 553 (90, (M+H)+). utyl {1 -[4-(8—bromo chlorophenylimidazo[1,2- b]pyridazin yl)phenyl]cyclobutyl}carbamate UPLC-MS (Method 3): RT = 1.54 min; m/z (rel intensity) 475 (100, (M+H)+), 949 (50, (2M+H)+). 1H-NMR (d6-DMSO): 6 0.99- tert-Butyl {1 -[4-(6—chloro 1.35 (br m, 9H), 1.65-1.80 (m, phenylimidazo[1,2-b]pyridazin- 1H), 1.86-2.01 (m, 1H), 2.26- 2.39 m, 4H), 7.29 (d, J=8.5 Hz, yl)phenyl]cyclobutyl}carbamate 2H), 7.38 (d, J=9.4, 1H), 7.45- 7.60 (m, 7H), 8.25 (d, J=9.4 Hz, 1H).

UPLC-MS (Method 3): RT = 1.32 min; m/z (rel intensity) 456 (100, (M+H)+), 911 (50, +); ES— m/z (rel intensity) 454 (100, (M-H)'), 911 tert-Butyl {1 -[4-(6—amino (10, (2M-H)'). phenylimidazo[1,2-b]pyridazin- ediate Structure/ Name Characterization Example 2- 1H-NMR(d6-DMSO):61.00- yl)phenyl]cyclobutyl}carbamate 1.35 (br m, 9H), 1.65-1.77 (m 1H), 1.86-1.88 (m, 1H), 2.24- 2.38 (m, 4H), 6.27 (s, 2H), 6.64 (d, J=9.6 Hz, 1H), 7.29 (d, J=8.3 Hz, 2H), 7.37-7.50 (m 7H), 7.74 (d, J=9.4 Hz, 1H).

Cf-C. UPLC-MS (Method 3): RT = 1.60 min; m/z (rel intensity) 487 (100, (M+H)+), 973 (30, (2M+H)+). 1H-NMR(d6-DMSO):61.00- tert- Buty|((1-{ [6- 1.37 (br m, 9H), 1.68-1.79 (m (methylsulfanyI) 1H), 1.88-2.00 (m, 1H), 2.27- phenylimidazo[1,2-b]pyridazin- 2.38 (m, 4H), 2.43 (s, 3H), 7.18 (d, J=9.6 Hz, 1H), 7.29 (d, yl]phenyl}cyclobutyl)carbamate J=8.3 Hz, 2H), .49 (m 3H), 7.52 (d, J=8.3 Hz, 2H), 7.57 (dm; J=7.6 Hz, 2H), 7.98 (9.6 Hz, 1H).

Cir UPLC-MS (Method 3): RT = 1.55 min; m/z (rel ity) 519 (90, (M+H)+). 1H-NMR (d6-DMSO): 6 0.98- 1.32 (m, 9H), 1.65-1.79 (m tert- Butyl {1 -[-4((6- bromo 1H), 1.85-2.00 (m, 2H), 2.26- phenylimidazo[1,2-b]pyridazin- 2.39 (m, 4H), 7.29 (d, J=8.5 Hz, 2H), 7.45 (d, J=9.4 Hz, 1H), yl)phenyl]cyclobutyl}carbamate 7.47-7.57 (m, 7H), 8.14 (9.4 Hz, 1H).

Intermediate ure/ Name Characterization Example UPLC-MS (Method 3): RT = "Cf/NI: 1.39 min; m/z (rel intensity) 456 (100, (M+H)+), 911 (20, (M+H)+); ES- m/z (rel intensity) 454 (90, (M-H)'). tert- Butyl {1 -[-4((8-a—mino-3—- phenylimidazo[1,2-b]pyridazin- yl)phenyl]cyc|obuty|}carbamate Intermediate Example Int-7: utyl (1 -{4-[3-phenylbromomethoxyimidazo[1 ,2-b]pyridazinyl]- phenyl}cyclobutyl)carbamate CIZ CH3 A solution of tert- buty|((1-{ [3- phenyl--6, 8--dibromoimidazo[1, 2-b—]pyridazin- yl]pheny|}cyc|obutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-6 (0.10 g, 0.17 mmol in MeOH (3 mL) was cooled with an ice bath and treated dropwise with sodium methoxide (0.5 M in MeOH, 0.40 mL, 0.20 mmol, 1.2 eq). The resulting solution was allowed to warm to room temperature and was stirred at room temperature for 2 h, after which additional sodium ide was added (0.5 M in methanol, 0.40 mL, 0.20 mmol, 1.2 eq). The resulting solution was d to warm to room temperature and was stirred at room temperature for 2 h, after which additional sodium methoxide was added (0.5 M in MeOH, 0.40 mL, 0.20 mmol, 1.2 eq).

The resulting solution was added to ice water, and the aqueous mixture was extracted with DCM (3 x 25 mL). The combined organic phases were dried (NazSO4 anh.) and concentrated under reduced pressure to give impure tert- butyl (1 -{4-[3-phenylbromomethoxyimidazo[1 ,2-b]pyridazin yl]phenyl}cyc|obutyl)carbamate (102 mg, ~78% pure). This material was used without further purification: S (Method 3): RT = 1.67 min; m/z (rel intensity) 549 (90, ). 1H-NMR (d6-DMSO): 5 100-120 (br s, 3H), 1.20-1.37 (br s, 6H), 1.65-1.81 (br s, 1H), 1.85-2.00 (m, 1H), 2.25-2.38 m, 4H), 3.80 (s, 3H), 6.92 (d, J=9.6 Hz, 1H), 7.28 (d, J=8.5 Hz, 2H), 7.37-7.59 (m, 8H), 8.50 (d, J=9.6 H, 1H).

The following examples were prepared in a manner analogous to ediate Example Int-7 by reacting the appropriate carbamate with sodium methoxide in methanol Intermediate ure/ Name Characterization Example Int-7.1 UPLC-MS (Method 3): RT = 1.62 min; m/z (rel ity) 548 (100, (M+H)+). tert-Butyl (1 -{4-[6-methoxy phenyl(pyridin yl)imidazo[1,2-b]pyridazin yl]phenyl}cyc|obutyl)carbamate Int-7.2 UPLC-MS (Method 3): RT = 1.60 min; m/z (rel intensity) 537 (100, (M+H)+); ES- m/z (rel intensity) 535 (100, (M-H)'). tert-Butyl (1 -{4-[6-methoxy phenyl(1 H-pyrazol dazo[1,2-b]pyridazin yl]phenyl}cyc|obutyl)carbamate Intermediate Structure/ Name Characterization Int-7.3 . :1 CH3 UPLC-MS (Method 3): RT = CH O N O+CH3 1.53 min; m/z (rel intensity) 505 I 3 H CH O 3 >>: The following examples were prepared in a manner analogous to Intermediate e Int-7 by reacting the appropriate carbamate with sodium ethoxide in ethanol Intermediate Structure/ Name Characterization Example Int-7.4 arr UPLC-MS (Method 3): RT = 1.61 min; m/z (rel intensity) 563 (90, (M+H)+)¢ ES- m/z (rel intensity) 561 (5, (M-H)'). tert- Butyl {1 6- bromo ethoxyphenylimidazo[1,2- b]pyridazin-2— yl)phenyl]cyc|obuty|}carbamate Intermediate Example Int-8: tert-Butyl (1 -{4-[3-phenyl-6,8-dimethoxyimidazo[1 ,2-b]pyridazinyl]- phenyl}cyclobutyl)carbamate 51:! A solution of tert- buty|((1-{ [3- phenyl--6, 8--dibromoimidazo[1, yridazin- yl]pheny|}cyc|obutyl)carbamate that was prepared in a manner us to that described for Intermediate Example Int-6 (0.66 g, 1.10 mmol) in MeOH (10 mL) was treated dropwise with sodium methoxide (0.5 M in MeOH, 11.0 mL, 5.51 mmol, 5.0 eq) and the resulting mixture was stirred at room temperature for 12 h. The resulting solution was irradiated at 120 °C in a microwave apparatus for 90 minutes. The ing solution was added to ice water, and the s mixture was ted with DCM (3 x 50 mL). The combined organic phases were dried (NazSO4 anh.) and concentrated under reduced pressure. The resulting material was purified using MPLC (Biotage Isolera; SNAP 10g cartridge: 100% hexane 2.0 min., gradient to 70% hexane /30% DCM 3 min., 70% hexane /30% DCM 3 min., nt to 50% hexane /50% DCM 4 min., 50% hexane /50% DCM 3.5 min., gradient to 95% hexane /5% DCM 5.5 min., 95% hexane /5% DCM 5.5 min.) to give tert-butyl (1 -{4-[3-phenyI-6,8- dimethoxyimidazo[1,2-b]pyridazinyl]pheny|}cyc|obuty|)carbamate (0.19 g, 34%) followed by methyl (1-{4-[3-phenyI-6,8-dimethoxyimidazo[1,2-b]pyridazin- 2-yl]pheny|}cyc|obutyl)carbamate (0.029 g, 5.4%). tert-Butyl (1 -{4-[3-phenyI-6,8-dimethoxyimidazo[1 ,2-b]pyridazinyl]phenyl}- cyclobutyl)carbamate: UPLC-MS (Method 3): RT = 1.53 min; m/z (rel intensity) 501 (50, (M+H)+). 1H-NMR (d6—DMSO): 6 1.00-1.18 (br s, 3H), 1.22-1.35 (br s, 6H), 1.67-1.79 (br s, 1H), .98 (br s, 1H), 2.27-2.37 (m, 4H), 3.77 (s, 3H), 4.20 (s, 3H), 6.41 (s, 1H), 7.26 (d, J=8.3 Hz, 2H), 7.38-7.48 (m, 5H), 7.52-7.56 (m, 2H).

Methyl (1 -{4-[3-phenyl-6,8-dimethoxyimidazo[1 ,2-b]pyridazinyl]phenyl}- cyclobutyl)carbamate: UPLC-MS (Method 3): RT = 1.36 min; m/z (rel intensity) 459 (70, (M+H)+); ES- m/z (rel intensity) 457 (10, (M-H)'). 1H-NMR (d6-DMSO): 6 1.66-1.81 (m, 1H), 1.86-2.02 (br s, 1H), 2.35 (br t, J=7.3 Hz, 4H), 3.41 (br s, 3H), 3.76 (s, 3H), 4.20 (s, 3H), 6.41 (s, 1H), 7.26 (d, J=8.3 Hz, 2H), 7.38-7.51 (m, 5H), 7.51-7.57 (m, 2H), 7.87 (br s, 1H).

Intermediate Example Int-9: Methyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}pheny|)methoxy- 3-phenylimidazo[1,2-b]pyridazinecarboxylate To a solution of tert-butyl (1-{4-[3-pheny|—6-bromomethoxyimidazo[1,2- daziny|]pheny|}cyc|obuty|)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-7 (0.41 g, 0.75 mmol) in MeOH (10 mL) and THF (1 mL) in an autoclave was added 1,1’- bis(diphenylphosphino)ferrocenepalladium(ll) dichloride (0.12 g, 0.15 mmol, 0.20 equiv) and triethylamine (0.11 mL, 0.82 mmol, 1.1 equiv.). The ave was flushed with CO (approximately 5 bar) three times, then was pressurized with CO (5.2 bar), stirred at room temperature 30 min., and y placed under reduced atmosphere (0.06 bar). The autoclave was then pressurized with CO (5.9 bar at 20 °C), heated to 110 °C, and stirred at this temperature for 22 h.

The resulting solution was concentrated under reduced pressure. The resulting material was crystallized from MeOH to give methyl 2-(4-{1-[(tert- butoxycarbonyl)amino]cyc|obutyl}phenyI)methoxyphenylimidazo[1,2- b]pyridazinecarboxylate (0.34 g, 85%): UPLC-MS (Method 3): RT = 1.46 min; m/z (rel intensity) 529 (70, ); ES- m/z (rel ity) 527 (5, (M-H)'). 1H-NMR (d6-DMSO): 5 1.00-1.18 (br s, 3H), 1.22-1.35 (br s, 6H), 1.67-1.79 (br s, 1H), 1.87-1.98 (br s, 1H), 2.27-2.37 (m, 4H), 3.77 (s, 3H), 4.20 (s, 3H), 6.41 (s, 1H), 7.25 (d, J=8.3 Hz, 2H), 7.38-7.48 (m, 5H), 7.52-7.56 (m, 2H). ediate Example Int-10: utyl {1 -[4-(6-carbamoylmethoxyphenylimidazo[1 ,2-b]pyridazin yl)phenyl]cyclobutyl}carbamate (Approach 1) o )1 CH N O+CH / 3 3 0 CH3 / I ‘N O A mixture of methyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyc|obuty|}phenyI) methoxyphenylimidazo[1,2-b]pyridazinecarboxylate that was prepared in a manner analgous to that described for Intermediate e Int-9 (0.20 g, 0.38 mmol) in a solution of ammonia in MeOH (7 N, 15 mL) and THF (1 mL) was irradiated in a microwave apparatus at 130 °C for 90 min. The solids were collected by tion to give tert-butyl {1 -[4-(6-carbamoyImethoxy phenylimidazo[1,2-b]pyridazinyl)pheny|]cyc|obuty|}carbamate (0.12 g, 63%): UPLC-MS (Method 3): RT = 1.30 min; m/z (rel intensity) 514 (70, (M+H)+); ES- m/z (rel intensity) 512 (90, (M-H)'). 1H-NMR (d6—DMSO): 5 100-120 (br s, 3H), 1.20-1.39 (br s, 6H), 1.65-1.81 (br s, 1H), 1.86-2.02 (br m, 1H), 2.28-2.39 (m, 4H), 3.77 (s, 3H), 4.13 (s, 3H), 7.15 (s, 1H), 7.30 (d, J=8.3 Hz, 2H), 7.41-7.55 (m, 7H), 7.56-7.62 (m, 2H), 7.82 (br s, 1H).

The following examples were prepared in a manner ous to Intermediate Example Int-10 by reacting the appropriate carbamate with a solution of ammonia in MeOH: 2012/056300 Intermediate Structure/ Name Characterization Example Int-10.1 UPLC-MS (Method 3): RT = 1.29 min; m/z (rel intensity) 558 (100, (M+H)+); ES- m/z (rel intensity) 556 (100, (M-H)'). tert-Butyl (1 -{4-[6-carbamoy|—8— (2—methoxyethoxy) phenylimidazo[1,2—b]pyridazin- yl]phenyl}cyclobutyl)carbamate The following examples were prepared in a manner analogous to Intermediate Example Int-1O by ng the appropriate carbamate with a on of methylamine in MeOH: Intermediate Structure/ Name Characterization Example Int-10.2 UPLC-MS (Method 3): RT = 1.42 min; m/z (rel intensity) 542 (70, ); ES— m/z (rel intensity) 540 (30, (M-H)'). tert-Butyl (1 -{4-[8-ethoxy (methylcarbamoyI) phenylimidazo[1,2—b]pyridazin- yl]phenyl}cyclobutyl)carbamate Intermediate Structure/ Name Characterization Example Int-10.3 UPLC-MS (Method 3): RT = 1.35 min; m/z (rel intensity) 527 (70, (M+H)+); ES— m/z (rel intensity) 525 (20, (M-H)'). tert-Butyl (1 -{4-[8-methoxy-6— (methylcarbamoyI) imidazo[1,2-b]pyridazin- yl]phenyl}cyc|obuty|)carbamate Intermediate Example Int-11: tert-Butyl {1 -[4-(8-methoxyphenylimidazo[1 ,2-b]pyridazinyl)— phenyl]cyclobutyl}carbamate CH3H3 To a mixture of tert- buty|((1-{ [3- phenyl---6bromo-methoxyimidazo[1, 2- b]pyridaziny|]pheny|}cyc|obuty|)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-7 (0.075 g, 0.14 mmol) and 5% palladium on carbon (0.007 g) in DMF (1 mL) was added a solution of sodium formate (0.074 g, 1.09 mmol, 8.0 eq) in water (0.2 mL). The resulting mixture was stirred at 80 °C for 3 h, diluted with MeOH (10 mL) and stirred at room temperature for 1 h. The ing solution was ed through a membrane filter, and the solids were washed with MeOH (1 mL). The resulting solution was diluted with EtOAc (25 mL), washed with water (2 x 25 mL), dried (Na2804 anh.) and concentrated under d pressure to give tert-butyl {1 -[4- (8—methoxyphenylimidazo[1,2—b]pyridazin-2—yl)phenyl]cyclobutyl}carbamate approximately 75% purity (0.058 g, 90%): UPLC-MS (Method 3): RT = 1.44 min; m/z (rel intensity) 471 (100, (M+H)+); ES- m/z (rel intensity) 512 (90, (M-H)').

The following es were prepared in a manner analogous to Intermediate e Int-11 by reacting the appropriate carbamate with sodium formate and a palladium catalyst Intermediate Structure/ Name Characterization Example Int-11.1 . o UPLC-MS (Method 3): RT = n i 1.33 min; m/z (rel ity) 441 (<3 1 "30 CHEHS (100, (M+H)+), 881 (50, -N’ O (2M+H)+); ES— m/z (rel ity) 439 (100, (M-H)'), 879 tert-Butyl {1 -[4-(3- (10, (2M-H)'). imidazo[1,2—b]pyridazin- yl)phenyl]cyclobutyl}carbamate Int-11.2 UPLC-MS (Method 3): RT = 1.49 min; m/z (rel intensity) 507 (100, (M+H)+); ES- m/z (rel intensity) 505 (100, (M-H)'). tert-Butyl (1 -{4-[3-phenyl (1 H-pyrazolyl)imidazo[1,2- b]pyridazin yl]phenyl}cyclobutyl)carbamate Int-11.3 UPLC-MS (Method 3): RT = 0.83 min; m/z (rel intensity) 457 (100, (M+H)+), 913 (70, (2M+H)+); ES— m/z (rel intensity) 455 (100, (M-H)').

Intermediate Structure/ Name Characterization Example tert-Butyl {1 -hydroxy phenylimidazo[1,2—b]pyridazin- yl)phenyl]cyc|obuty|}carbamate Int-11.4 UPLC-MS (Method 3): RT = 1.49 min; m/z (rel intensity) 535 (100, (M+H)+); ES- m/z (rel intensity) 533 (100, (M-H)'). utyl (1 -{4-[8-(4- fluorophenyI) phenylimidazo[1,2—b]pyridazin- yl]phenyl}cyc|obuty|)carbamate Intermediate Example Int-12: tert-Butyl {1 -[4-(8-methoxyphenylvinylimidazo[1 yridazinyl)- phenyl]cyclobutyl}carbamate . 0 CH3 mic 3 A mixture of tert-butyl (1 -{4-[3-phenyIbromomethoxyimidazo[1 ,2- b]pyridaziny|]pheny|}cyc|obuty|)carbamate that was prepared in a manner us to that described for Intermediate Example Int-7 (0.30 g, 0.54 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.006 g, 0.005 mmol, 10 mol%) in 1,2—dimethoxyethane (4 mL) was stirred under an argon atmosphere for 10 min, then was tially treated with K2C03 (0.075 g, 0.54 mmol, 1.0 eq), water (1.5 mL) and vinylboronic acid anhydride pyridine complex (prepared as described in J. Org. Chem. 2002, 67, 4968; 0.13 g, 0.54 mmol, 1.0 eq). The resulting mixture was heated at the reflux temperature for 16 h, then was added to water (15 mL). The ing mixture was extracted with EtOAc (2x25 mL).

The ed organic phases were washed with water (25 mL), dried (NazSO4), and concentrated under reduced pressure. The resulting material was purified using MPLC (Biotage |so|era; Snap 10g cartridge, 100% hexane 1.5 min, gradient to 80% hexane / 20% EtOAc 1.0 min, 80% hexane / 20% EtOAc 2.0 min, gradient to 50% hexane / 50% EtOAc 3.0 min, 50% hexane / 50% EtOAc 4.0 min, gradient to 100% EtOAc 4.5 min, 100% EtOAc 7.7 min) to give tert- butyl {1-[4-(8—methoxyphenylvinylimidazo[1,2-b]pyridazin yl)phenyl]cyclobutyl}carbamate (0.25 g, 92%): UPLC-MS (Method 3): RT = 1.55 min; m/z (rel intensity) 497 (100, (M+H)+); ES- m/z (rel intensity) 495 (10, (M-H)'). 1H-NMR (d6—DMSO): 6 0.80-1.37 (br m, 9H), 1.65-1.80 (br s, 1H), 1.85-2.01 (br m, 1H), 2.27-2.37 (m, 4H), 4.02 (s, 3H), 5.63 (d, J=11.3 Hz, 1H), 6.27 (d, J=17.7 Hz, 1H), 6.64 (dd, J=10.0, 17.7 Hz, 1H), 7.04 (s, 1H), 7.27 (d, J=8.5 Hz, 2H), 7.42-7.55 (m, 8H).

The ing examples were prepared in a manner analogous to ediate Example Int-12 by reacting the appropriate carbamate with vinylboronic acid anhydride pyridine complex Intermediate Structure/ Name Characterization Example Int-12.1 S (Method 3): RT = 1.71 min; m/z (rel intensity) 493 (100, (M+H)+), 985 (80, (2M+H)+); ES— m/z (rel intensity) 491 (10, (M-H)'). tert-Butyl {1 -[4-(3-phenyl-6,8- divinylimidazo[1,2-b]pyridazin- yl)phenyl]cyclobutyl}carbamate ediate Structure/ Name Characterization Example Int-12.2 UPLC-MS (Method 3): RT = 1.59 min; m/z (rel intensity) 533 (100, (M+H)+); ES- m/z (rel intensity) 531 (100, (M-H)'). tert-Butyl (1 -{4-[3-phenyI (1 H-pyrazoIyI) vinylimidazo[1 ,2—b]pyridazin-2— yl]phenyl}cyc|obuty|)carbamate Intermediate Example Int-13: tert-Butyl {1 -[4-(6-ethylmethoxyphenylimidazo[1 ,2-b]pyridazinyl)- phenyl]cyclobutyl}carbamate A solution of tert- butyl {1 -[-4((8-methoxy phenyl--viny|imidazo[1, 2-b—]pyridazin- 2—yl)pheny|]cyc|obutyl}carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-12 (0.20 g, 0.40 mmol) in methanol (8 mL) was hydrogenated using an H-Cube flow reactor (Pd/C cartridge). The resulting solution was trated under reduced re to give tert-butyl {1 - [4-(6-ethyImethoxyphenylimidazo[1 yridazin-2— yl)pheny|]cyc|obutyl}carbamate (0.20 g, 100%): 1H-NMR (d6—DMSO): 0 108-135 (br m, 9H), 1.19 (t, J=7.5 Hz,3H), 1.66-1.83 (br s, 1H), .03 (br m, 1H), 2.26-2.37 (m, 4H), 2.68 (q, J=7.5 Hz, 2H), 4.05 (s, 3H), 6.70 (s, 1H), 7.26 (d, J=8.5 Hz, 2H), 7.41-7.53 (m, 8H).

The following examples were prepared in a manner analogous to Intermediate Example Int-13 by hydrogenation of the appropriate ate using an H- Cube flow reactor Intermediate Structure/ Name Characterization UPLC-MS (Method 3): RT = 1.77 min; m/z (rel intensity) 497 (100, (M+H)+). tert-Butyl {1 -[4-(6,8—diethyl phenylimidazo[1,2—b]pyridazin- yl)phenyl]cyclobutyl}carbamate Int-13.2 UPLC-MS (Method 3): RT = 1.62 min; m/z (rel intensity) 535 (100, (M+H)+); ES- m/z (rel intensity) 533 (50, ). tert-Butyl (1 -{4-[6-ethyl phenyl(1 H-pyrazol yl)imidazo[1,2—b]pyridazin-2— yl]phenyl}cyclobutyl)carbamate Intermediate Example Int-14: utyl (1 -{4-[6-chlorophenyl(pyridinyl)imidazo[1 ,2-b]pyridazin yl]phenyl}cyclobutyl)carbamate A mixture of tert-butyl {1 -[4-(8-bromochlorophenylimidazo[1 yridazin- 2-y|)pheny|]cyc|obutyl}carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-7.1 (0.15 g, 0.27 mmol), 3- pyridineboronic acid (0.040 g, 0.33 mmol, 1.2 equiv.), 1,1 '- bis(diphenylphosphino)ferrocenepalladium(I|) dichloride (0.022 g, 0.03 mmol, 0.1 ), Na2C03 (0.086 g, 0.81 mmol, 3.0 equiv.), in dioxane (2.9 mL) and water (0.4 mL) was bubbled with Ar, then placed under an argon atmosphere and was irradiated in a microwave apparatus at 105 °C for 90 min. The reaction e was then added to a mixture of water (10 mL), a ted aqueous NH4CI solution (10 mL) and CH2C|2 (20 mL). The resulting e was stirred strongly for 30 minutes. The organic phase was separated, dried (Na2804 anh), and concentrated under reduced pressure. The resulting material was purified using MPLC (Biotage Isolera; Snap 10g cartridge, 100% hexane 2.0 min, gradient to 80% hexane / 20% EtOAc 1.0 min, 80% hexane/ % EtOAc 3.0 min, nt to 50% hexane / 50% EtOAc 2.5 min, 50% hexane /50% EtOAc 3.5 min, gradient to 100% EtOAc 3.0 min, 100% EtOAc 4.8 min) to give tert-butyl (1 -{4-[6-ch|oropheny|(pyridinyl)imidazo[1 ,2-b]pyridazin yl]pheny|}cyc|obutyl)carbamate (0.046 g, 31%): UPLC-MS (Method 3): RT = 1.62 min; m/z (rel intensity) 552 (100, (M+H)+); ES- m/z (rel intensity) 550 (10, (M-H)'). 1H-NMR (d6-DMSO): 6 0.98-1.37 (br m, 9H), 1.66-1.81 (br s, 1H), 1.85-2.00 (br m, 1H), 2.27-2.38 (m, 4H), 7.31 (d, J=8.5 Hz, 2H), 7.49-7.58 (m, 7H), 7.64 (ddd, J=7.0, 4.7, 0.8 Hz, 1H), 7.85 (s, 1H), 8.75 (ddd, J=4.9, 1.5 Hz, 1H), 8.81 (app dt, J=8.1, 1.9 Hz, 1H), 9.56 (dd, J: 2.3, 0.6 Hz, 1H).

The following es were prepared in a manner analogous to Intermediate Example Int-14 by reacting the appropriate carbamate with [1 -(tert- butoxycarbonyI)-1H-pyrazolyl]boronic acid Intermediate ure/ Name Characterization Example Int-14.1 UPLC-MS (Method 3): RT = 1.55 min; m/z (rel intensity) 541 (100, (M+H)+); ES- m/z (rel intensity) 539 (80, (M-H)'). tert-Butyl (1 -{4-[6-chloro phenyI(1 zoI yl)imidazo[1,2—b]pyridazin-2— yl]phenyl}cyclobutyl)carbamate The following examples were prepared in a manner analogous to ediate Example Int-14 by reacting the appropriate carbamate with [1 -(tertbutoxycarbonyI )-1H-pyrazolyl]boronic acid Intermediate Structure/ Name Characterization Example Int-14.2 UPLC-MS (Method 3): RT = 1.59 min; m/z (rel intensity) 541 (100, ); ES- m/z (rel intensity) 539 (50, (M-H)'). 1H-NMR(d6—DMSO):61.00- tert-Butyl (1 -{4-[6-chloro 1.37 (br m, 9H), 1.68-1.80 (br s, (1 H-pyrazoI 1H), 1.88-2.00 (br m, 1H), 2.30- yl)imidazo[1,2—b]pyridazin-2— 2.38 (m, 3H), 7.32 (d, J=8.6 Hz, yl]phenyl}cyclobutyl)carbamate 2H), 7.49-7.56 (m, 5H), 7.61 (br d, J=8.1 Hz, 2H), 7.20-7.70 (m, 2H), 7.98 (br s, 1H).

WO 36776 The following examples were prepared in a manner analogous to Intermediate Example Int-14 by reacting the appropriate carbamate with (1 -methyI-1 H- pyrazolyl)boronic acid Intermediate Structure/ Name Characterization Example Int-14.3 UPLC-MS (Method 3): RT = 1.59 min; m/z (rel intensity) 555 (80, (M+H)+); ES— m/z (rel intensity) 553 (20, (M-H)'). 1H-NMR(d6—DMSO):61.00- tert-Butyl (1 -{4-[6-chloro(1 - 1.37 (br m, 9H), 1.65-1.80 (br s, methyl-1H-pyrazoIyI) 1H), .89 (br m, 1H), 2.26- phenylimidazo[1,2—b]pyridazin- 2.38 (m, 4H), 4.05 (s, 3H), 6.92 (br s, 0.7 H), 7.30 (d, J=8.5 Hz, yl]phenyl}cyclobutyl)carbamate 2H), 7.49-7.57 (m, 8H), 7.64 (d, J=2.0 Hz, 1H), 7.20-7.70 (m, 2H), 7.96 (s, 0.3H).

The ing examples were prepared in a manner analogous to Intermediate Example Int-14 by reacting the appropriate carbamate with (4- fluorophenyl)boronic acid Intermediate Structure/ Name Characterization Example .4 UPLC-MS (Method 3): RT = 1.64 min; m/z (rel intensity) 535 (100, (M+H)+); ES- m/z (rel intensity) 533 (10, (M-H)'). utyl (1 -{4-[6-(4- Intermediate Structure/ Name Characterization Example fluorophenyI) phenylimidazo[1,2—b]pyridazin- yl]phenyl}cyclobutyl)carbamate .5 UPLC-MS (Method 3): RT = 1.77 min; m/z (rel intensity) 569 (100, (M+H)+). tert-Butyl (1 -{4-[6-ch|oro-8—(4- fluorophenyI) phenylimidazo[1,2—b]pyridazin- yl]phenyl}cyclobutyl)carbamate The following examples were prepared in a manner analogous to Intermediate Example Int-14 by ng the appropriate carbamate with cyclopropylboronic acid Intermediate Structure/ Name Characterization Example Int-14.6 S d 3): RT = 1.70 min; m/z (rel intensity) 515 (100, (M+H)+). tert-Butyl {1 -[4-(6—ch|oro cyclopropyI phenylimidazo[1,2—b]pyridazin- yl)phenyl]cyclobutyl}carbamate The following examples were prepared in a manner ous to Intermediate Example Int-14 by ng the appropriate carbamate with pyridinylboronic acid Intermediate Structure/ Name Characterization Example Int-14.7 UPLC-MS (Method 3): RT = 1.63 min; m/z (rel ity) 596 (100, (M+H)+). 1H-NMR(d6—DMSO):61.00- 1.00-1.38 (m, 9H), 1.66—1.80 (br tert-butyl (1 -{4-[6-bromo s, 1H), 1.85-2.00 (br m, 1H), phenyI(pyridin 2.28-2.38 (m, 4H), 7.32 (d, yl)imidazo[1,2-b]pyridazin J=8.5 Hz, 2H), 7.47-7.58 (m yl]phenyl}cyclobutyl)carbamate 8H), 7.94 (s, 1H), 8.39 (dm, J=6.2 Hz, 2H), 8.81 (dm, J=6.0 Hz, 2H).

Intermediate Example Int-15: 2-(4-{1-[(tert-Butoxycarbonyl)amino]cyclobutyl}phenyl)—3-phenyl- imidazo[1,2-b]pyridazin-8—yl trifluoromethanesulfonate To a solution of tert-butyl {1- [4-((8--h-ydroxy-phenylimidazo[1, 2-b-]pyridazin- yl)phenyl]cyclobutyl}carbamate that was prepared in a manner analgous to that described for Intermediate e Int-11.3 (0.34 g, 0.75 mmol) and triethylamine (0.25 mL, 1.73 mmol, 2.3 equiv.) in DCM (3 mL) at -20 °C under argon was added dropwise oromethanesulfonic anhydride (0.15 mL, 0.90 mmol, 1.2 equiv.). The reaction e was allowed to slowly warm to room temperature, was d for 1 h,and was cooled to -10 °C. onal triethylamine (0.25 mL, 1.73 mmol, 2.3 equiv.) and trifluoromethanesulfonic anhydride (0.15 mL, 0.90 mmol, 1.2 equiv.) was added. The mixture was allowed to warm to room temperature and was stirred for 3 h. The mixture was treated with a 50% water / 50% saturated NaHC03 solution (10 mL). The aqueous mixture was extracted with DCM (3 x 10 mL), dried (Na2804 anh.), and concentrated under reduced pressure. The resulting material was purified using MPLC ge a; Snap 10g cartridge, 100% hexane 2.0 min, gradient to 80% hexane / 20% EtOAc 1.0 min, 80% hexane / 20% EtOAc 3.0 min, gradient to 50% hexane / 50% EtOAc 3.5 min, 50% hexane / 50% EtOAc 4.0 min, gradient to 100% EtOAc 3.5 min, 100% EtOAc 4.5 min) to give 2-(4-{1-[(tert- butoxycarbonyl)amino]cyclobutyl}phenyl)phenylimidazo[1,2-b]pyridazinyl trifluoromethanesulfonate (0.15 mg, 34%): UPLC-MS (Method 3): RT = 1.63 min; m/z (rel intensity) 588 (40, (M+H)+); ES- m/z (rel intensity) 587 (20, (M-H)'). 1H-NMR (d6-DMSO): 5 1.00-1.36 (br m, 9H), 1.68-1.80 (br s, 1H), 1.88-2.00 (br m, 1H), 2.30-2.38 (m, 4H), 7.33 (d, J=8.6 Hz, 2H), 7.47-7.57 (m, 7H), 7.62, (d, J=5.3 Hz, 1H), 8.60 (d, J=5.3 Hz, 1H).

Intermediate Example Int-16: tert-Butyl {1 -[4-(6-chlorohydroxyphenylimidazo[1 yridazinyl)- phenyl]cyc|obutyl}carbamate To a solution of tert-butyl {1- [4-((8-bromochloro-phenylimidazo[1, 2- b]pyridazinyl)phenyl]cyclobutyl}carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-6.1 (2.49 g, 4.50 mmol) in DMF (63 mL) was added potassium acetate (2.21 g, 22.5 mmol, 5.0 equiv.), and the resulting mixture was was irradiated in a ave apparatus at 140 °C for 90 min. The resulting mixture was added to ice water (200 mL). The water mixture was extracted with a 4:1 DCM / panol solution (4 x 50 mL).

The combined organic phases were dried (Na2804 anh.), and concentrated under reduced pressure to give a brown oil (2.6 g). The oil was triturated with MeOH to give tert-butyl {1 -[4-(6-chlorohydroxyphenylimidazo[1 ,2- b]pyridazinyl)phenyl]cyclobutyl}carbamate as a yellow powder (0.60 g, 27%): S (Method 3): RT = 0.93 min; m/z (rel intensity) 491 (100, (M+H)+), 981 (80 (2M+H)+); ES— m/z (rel ity) 489 (100, (M-H)'). 1H-NMR (d6-DMSO): 6 1.00-1.35 (br m, 9H), 1.65-1.80 (br s, 1H), 1.86-1.99 (br m, 1H), 2.25-2.39 (m, 5H), 6.45 (s, 1H), 7.29 (d, J=8.7 Hz, 2H), .52 (m 8H).

Intermediate Example Int-17: tert-Butyl (1 -(benzy|oxy)ch|orophenylimidazo[1 ,2-b]pyridazin yl]phenyl}cyclobutyl)carbamate To a solution of tert-butyl {1- [4-((-6chloro hydroxy phenylimidazo[1, 2- b]pyridazinyl)phenyl]cyclobutyl}carbamate that was in a manner analgous to that described for Intermediate Example Int-16 (1.90 g, 3.87 mmol) in DMF (50 mL) was added cesium carbonate (6.88 g, 11.6 mmol, 3.0 equiv.) and benzyl bromide (0.58 mL, 4.84 mmol, 1.25 equiv.), and the ing mixture was irradiated in a microwave apparatus at 140 °C for 90 min. The ing mixture stirred at room temperature for 16 h. The resulting e was added to ice water 100 mL). The aqueous mixture was extracted with a 4:1 DCM/ isopropanol solution (3 x 50 mL). The combined organic phases were dried (Na2804 anh.), and concentrated under reduced pressure. The resulting oil was triturated with ethanol to give tert-butyl (1 -{4-[8-(benzyloxy)chloro phenylimidazo[1,2-b]pyridazinyl]phenyl}cyclobutyl)carbamate as a powder (0.93 g, 41%): UPLC-MS (Method 3): RT = 1.51 min; m/z (rel intensity) 581 (100, (M+H)+); ES- m/z (rel intensity) 579 (90, (M-H)'). 1H-NMR (d6-DMSO): 6 0.98-1.35 (br m, 9H), 1.64-1.78 (br s, 1H), 1.84-2.00 (br m, 1H), 2.25-2.37 (m, 4H), 5.48 (s, 2H), 7.08 (s, 1H), 7.26 (d, J=8.5 Hz, 2H), 7.37-7.57 (m, 13H).

Intermediate Example Int-18: Methyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)hydroxy phenylimidazo[1,2-b]pyridazine—6-carboxylate To a solution of tert-butyl (1 -{4-[8-(benzyloxy)ch|oropheny|imidazo[1 ,2- b]pyridaziny|]pheny|}cyc|obuty|)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-17 (0.91 g, 1.48 mmol) in MeOH (20 mL) and THF (2 mL) in an autoclave was added 1,1 ’- phenylphosphino)ferrocenepalladium(|I) dichloride (0.24 g, 0.30 mmol, 0.20 equiv) and triethylamine (0.23 mL, 1.63 mmol, 1.1 ). The autoclave was d with CO (approximately 5 bar) three times, then was pressurized with CO (5.2 bar), stirred at room temperature 30 min., and briefly placed under reduced atmosphere (0.06 bar). The autoclave was then pressurized with CO (5.9 bar at 20 °C), heated to 100 °C, and stirred at this temperature for 18 h.

The resulting solution was concentrated under d pressure. The resulting material was purified using MPLC (Biotage Isolera; Snap 25g cartridge, 100% hexane 2.0 min, gradient to 80% hexane / 20% EtOAc 1.0 min, 80% hexane/ % EtOAc 3.0 min, nt to 50% hexane / 50% EtOAc 6.0 min, 50% hexane /50% EtOAc 6.5 min, gradient to 10% hexane / 90% EtOAc 6.0 min, gradient to 100% EtOAc 2.7 min, 100% EtOAc 26.7 min) to give methyl 2-(4-{1-[(tert- butoxycarbonyl)amino]cyc|obutyl}phenyI)hydroxyphenylimidazo[1,2- b]pyridazinecarboxylate (0.34 g, 44%): S (Method 3): RT = 0.89 min; m/z (rel intensity) 515 (100, (M+H)+); ES- m/z (rel intensity) 513 (100, (M-H)').

Intermediate Example Int-19: Methyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)ethoxy phenylimidazo[1,2-b]pyridazine—6-carboxylate 9 fr OHS N o/1\CH3 H CH3 A mixture of methyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyc|obuty|}phenyI) hydroxyphenylimidazo[1,2-b]pyridazinecarboxylate that was in a manner analgous to that described for Intermediate Example Int-18 (0.16 g, 0.32 mmol), ethyl iodide (0.50 mL, 0.63 mmol, 2.0 equiv.) and cesuim carbonate (0.31 g, 0.94 mmol, 3.0 equiv.) in DMF (6 mL) was stirred for 1 h at room ature, followed by 3 h at 50 °C. The reaction mixture was then added to ice water (20 mL). The aqueous mixture was extracted with a 4:1 DCM / isopropanol solution (2 x 25 mL). The combined organic phases were dried (Na2804 anh.) and trated under reduced pressure. The resulting material was purified using MPLC (Biotage Isolera; Snap 10g cartridge, 80% hexane / 20% EtOAc 3.0 min, nt to 55% hexane / 45% EtOAc 2.0 min, 55% / 45% EtOAc 3.0 min, gradient to 4% hexane / 96% EtOAc 5.5 min, gradient to 100% EtOAc 0.5 min, 100% EtOAc 7.2 min) to give methyl 2-(4-{1-[(tert- butoxycarbonyl)amino]cyc|obuty|}phenyI)ethoxyphenylimidazo[1 ,2- b]pyridazinecarboxylate (0.072 g, 42%): UPLC-MS (Method 3): RT = 1.50 min; m/z (rel intensity) 543 (100, (M+H)+); ES- m/z (rel intensity) 541 (10, ).

The following examples were prepared in a manner analogous to Intermediate e Int-19 by reacting the appropriate phenol with 2-methoxyethyl bromide Intermediate Structure/ Name Characterization .1 UPLC-MS Method ( o—CHa . j]: H _ /NI +3 3 3 m/z (rel intensity) 573 Hag m" D (100, (M+H)+); ES- O m/z (rel intensity) 571 Methyl 2-(4-{1-[(tert- (2o, (M-H)'). butoxycarbonyl)amino]cyc|obuty|}phenyl)- 8—(2-methoxyethoxy) phenylimidazo[1,2-b]pyridazine carboxylate Intermediate Example Int-20: tert-Butyl (1-{4-[6-chloro(1H-imidazolyl)phenylimidazo[1,2-b]- pyridazinyl]phenyl}cyclobutyl)carbamate H3CHCH 3 A e of tert-butyl {1-[4-(8—bromochIorophenylimidazo[1,2-b]pyridazin- 2-y|)pheny|]cyc|obutyl}carbamate that was prepared in a manner analgous to that described for Intermediate e Int-7.1 (0.78 g, 1.42 mmol), 1H- imidazoIylboronic acid (0.024 g, 2.13 mmol, 1.5 equiv.), 1,1'- bis(diphenylphosphino)ferrocenepalladium(II) dichloride CDM complex (0.12 g, 0.14 mmol, 0.1 equiv.) and cesium de (0.65 g, 4.25 mmol, 3.0 equiv.) in dimethoxymethane (12 mL) was bubbled with Ar, then placed under an argon atmosphere in a sealed vial, and was heated at 100 °C for 3 days. The reaction mixture was then added to ice water (50 mL). The aqueous mixture was extracted with a 4:1 DCM / isopropanol solution (4 x 50 mL). The combined organics were dried (Na2804 anh.) and concentrated under reduced pressure.

The resulting material was purified using MPLC (Biotage Isolera; Snap 25g cartridge, 100% hexane 2.0 min, gradient to 50% hexane / 20% EtOAc 3.5 min, 50% hexane / 50% EtOAc 4.5 min, gradient to 100% EtOAc 5.0 min, 100% EtOAc 8.7 min) to give tert-butyl (1 -ch|oro(1 H-imidazoIyI) phenylimidazo[1,2-b]pyridazinyl]pheny|}cyc|obuty|)carbamate (0.28 g, 37%): UPLC-MS d 3): RT = 1.54 min; m/z (re| intensity) 541 (100, (M+H)+); ES- m/z (re| intensity) 539 (30, (M-H)'). 1H-NMR (d6—DMSO): 5 1.00-1.37 (br m, 9H), 1.68-1.80 (br s, 1H), .00 (br m, 1H), 2.27-2.39 (m, 4H), 7.27 (app q, J=0.8 Hz, 1H), 7.33 (d, J=8.6 Hz, 2H), 7.50-7.55 (m, 5H), 7.59 (d, J=8.6 Hz, 2H), 7.92 (s, 1H), 8.81 (app t, J=1.4 Hz, 1H), 9.28-9.29 (m, 1H).

Intermediate Example Int-21: tert—Butyl {1-[4-(6-carbamoyl-8—methoxy—3-phenylimidazo[1,2-b]pyridazin yl)phenyl]cyclobutyl}carbamate (Approach 2) To a solution of tert-butyl {1 -[4-(6-ch|oromethoxypheny|imidazo[1 ,2- b]pyridazinyl)pheny|]cyc|obuty|}carbamate that was prepared in a manner ana|gous to that described for Intermediate Example Int-7.3 (0.54 g, 1.00 mmol) in a solution of ammonia in MeOH (7 N; 5.7 mL, 40 mmol, 40 equiv.) in an autoclave was added 1 ,1’-bis(diphenylphosphino)ferrocenepa||adium(||) dichloride DCM complex (0.16 g, 0.20 mmol, 0.20 equiv). The autoclave was flushed with CO (approximately 5 bar) three times, then was pressurized with CO (5.2 bar), stirred at room ature 30 min., and briefly placed under d atmosphere (0.06 bar). The autoclave was then pressurized with CO (5.9 bar at 20 oC), heated to 100 °C, and stirred at this temperature for 18 h.

The ing material was filtered and concentrated under reduced pressure to give tert-butyl {1 -carbamoyImethoxyphenylimidazo[1 ,2-b]pyridazin yl)pheny|]cyc|obutyl}carbamate (0.29 g, 57%): UPLC-MS d 3): RT = 1.29 min; m/z (rel intensity) 514 (70, (M+H)+); ES- m/z (rel intensity) 512 (100, (M-H)').

Intermediate Example Int-22: Methyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)phenyl- imidazo[1 ,2-b]pyridazinecarboxylate To a solution of 2-(4-{1-[(tert-butoxycarbony|)amino]cyc|obuty|}phenyI) phenylimidazo[1,2-b]pyridaziny| trifluoromethanesulfonate that was prepared in a manner analgous to that described for Intermediate Example Int-15 (0.15 g, 0.25 mmol) in MeOH (0.4 mL) and THF (0.04 mL) in an autoclave was added 1,1 ’-bis(diphenylphosphino)ferrocenepalladium(|I) dichloride (0.040 g, 0.050 mmol, 0.20 equiv) and triethylamine (0.040 mL, 0.27 mmol, 1.1 equiv.). The autoclave was flushed with CO (approximately 5 bar) three times, then was pressurized with CO (5.2 bar), stirred at room temperature min., and briefly placed under reduced atmosphere (0.06 bar). The ave was then pressurized with CO (5.9 bar at 20 °C), heated to 100 °C, and stirred at this temperature for 18 h. The resulting on was concentrated under reduced pressure. The resulting material was purified using MPLC (Biotage Isolera; Snap 10g cartridge, 100% hexane 2.0 min, gradient to 80% hexane / 20% EtOAc 2.5 min, gradient to 70% hexane / 30% EtOAc 3.0 min, 70% hexane / 30% EtOAc 2.5 min, gradient to 50% hexane / 50% EtOAc 3.5 min, 50% hexane / 50% EtOAc 4.0 min, gradient to 100% EtOAc 1.0 min, 100% EtOAc 5.8 min) to give methyl 1-[(tert- butoxycarbonyl)amino]cyc|obutyl}phenyI)phenylimidazo[1,2-b]pyridazine carboxylate (0.081 g, 63%): UPLC-MS d 3): RT = 1.46 min; m/z (rel intensity) 499 (100, (M+H)+), 997 (70, (2M+H)+); ES- m/z (rel intensity) 497 (20, ). 1H-NMR (d6-DMSO): 6 .36 (br m, 9H), 1.65-1.81 (br s, 1H), 1.86-2.02 (br m, 1H), 2.26-2.38 (m, 4H), 3.98 (s, 3H), 7.31 (d, J=8.5 Hz, 2H), 7.46-7.58 (m, 8H), 7.64 (d, J=4.5 Hz, 1H), 8.58 (d, J=4.7 Hz, 1H).

Intermediate Example : Dimethyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)phenyl- imidazo[1,2-b]pyridazine-6,8—dicarboxylate o j’L N O+CH To a solution of utyl (1-{4-[3-pheny|—6,8-dibromoimidazo[1,2-b]pyridazin yl]pheny|}cyc|obutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-6 (0.51 g, 0.80 mmol) in MeOH (1.3 mL) and THF (0.13 mL) in an autoclave was added 1,1 ’- bis(diphenylphosphino)ferrocenepalladium(|I) ride (0.13 g, 0.16 mmol, 0.20 equiv) and triethylamine (0.12 mL, 0.88 mmol, 1.1 equiv.). The autoclave was flushed with CO (approximately 5 bar) three times, then was pressurized with CO (5.2 bar), stirred at room temperature 30 min., and briefly placed under reduced atmosphere (0.06 bar). The autoclave was then pressurized with CO (5.9 bar at 20 °C), heated to 100 °C, and stirred at this temperature for 18 h.

The resulting solution was concentrated under reduced pressure. The resulting material was filtered and concentrated under reduced pressure to give dimethyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyc|obuty|}phenyI)phenylimidazo[1,2- b]pyridazine-6,8-dicarboxylate (0.45 g, 100%), which was used without further purification: UPLC-MS (Method 3): RT = 1.46 min; m/z (rel intensity) 557 (100, (M+H)+).

Intermediate Example Int-24: tert-Butyl {1 -[4-(6,8-dicarbamoylphenylimidazo[1 ,2-b]pyridazinyl)- phenyl]cyclobutyl}carbamate (1) and 2-[4—(1-Aminocyclobutyl)phenyl] phenylimidazo[1,2-b]pyridazine-6,8-dicarboxamide (2, Approach 1) (1) (2) A solution of dimethyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyc|obuty|}phenyI) imidazo[1,2-b]pyridazine-6,8-dicarboxylate that was prepared in a manner us to that described for Intermediate Example Int-23 (0.45 g, 0.81 mmol) in a solution of ammonia in MeOH (7 N, 11.5 mL) was irradiated in a microwave apparatus at 130 °C for 90 min. The resulting mixture was concentrated under reduced pressure. The resulting material was purified using MPLC ge Isolera; Snap 25g cartridge, 100% DCM 4.5 min, gradient to 95% DCM / 5% MeOH 1.0 min, 95% DCM / 5% MeOH 5.0 min, gradient to 90% DCM / 10% MeOH 1.0 min, 90% DCM/10% MeOH 8.1 min, gradient to 80% DCM / 20% MeOH 2.0 min, 80% DCM / 20% MeOH 8.2 min) to give utyl {1-[4-(6,8- amoyI-B-phenylimidazo[1,2-b]pyridazinyl)pheny|]cyc|obuty|}carbamate (0.34 g, 8%) followed by 2-[4-(1-aminocyclobutyl)phenyl]—3-phenylimidazo[1,2- b]pyridazine-6,8-dicarboxamide (0.63 g, 18%). tert-Butyl {1 -[4-(6,8-dicarbamoylphenylimidazo[1 ,2-b]pyridazin yl)pheny|]cyc|obutyl}carbamate (1 ): UPLC-MS (Method 3): RT = 1.28 min; m/z (rel intensity) 527 (100, (M+H)+); ES- m/z (rel intensity) 525 (60, (M-H)'). 2-[4-(1-Aminocyclobutyl)phenyl]—3-phenylimidazo[1,2-b]pyridazine-6,8- dicarboxamide UPLC-MS (Method 3): RT = 1.02 min; m/z (rel ity) 410 (100 (M+H-17)+), 427 (70, (M+H)+), 853 (20, +); ES- m/z (rel intensity) 425 (100, ), 851 (10, (M-H)').

Intermediate Example Int-25: tert-Butyl {1 -[4-(6-acetamidophenylimidazo[1 ,2-b]pyridazinyl)— phenyl]cyclobutyl}carbamate . 0 CH3 H CH3 / I H3C C _N O o}.—N fNiO+CH3 To a solution of tert-butyl {1 -[4-(6-aminophenylimidazo[1 ,2-b]pyridazin yI)pheny|]cyc|obutyl}carbamate that was prepared in a manner analgous to that described for Intermediate e Int-6.3 (0.10 g, 0.22 mmol) in DCM (4 mL) was added ne (0.036 mL, 0.44 mmol, 2 equiv) and acetic anhydride (0.027 mL, 0.29 mmol, 1.3 equiv). The reaction mixture was stirred for 24 h at room temperature, additional acetic anhydride (0.042 mL, 0.44 mmol, 2.0 equiv) was dded and the reaction mixture was stirred at room temperature for an additional 24 h. The resulting mixture was trated under reduced pressure to give tert-butyl {1 -acetamidophenylimidazo[1 ,2-b]pyridazin yI)pheny|]cyc|obutyl}carbamate (0.11 g, 100%) which was used without further purification: UPLC-MS (Method 3): RT = 1.34 min; m/z (rel intensity) 498 (100, (M+H)+), 995 (60, (M+H)+); ES— m/z (rel intensity) 496 (50, (M-H)'), 993 (10, (2M-H)').

The following examples were prepared in a manner ous to Intermediate Example Int-25 by reacting tert-butyl {1-[4-(6—aminophenylimidazo[1,2- b]pyridazinyl)phenyl]cyc|obuty|}carbamate (Intermediate Example Int-6.3) or tert-butyl {1-[4-(8—aminophenylimidazo[1,2-b]pyridazin yI)pheny|]cyc|obutyl}carbamate (Intermediate Example Int-6.6) with the appropriate anhydride Intermediate Structure/ Name Characterization ’ JOL This material was used without characterization. / a F F }\l FN» _N O tert-Butyl [1 -(4-{3-phenyI [(trifluoroacetyl)amino]imidazo[1,2 -b]pyridazin-2— nyl)cyc|obutyl]carbamate This material was used without characterization.

HSC\ 0‘er tert-Butyl [1-(4-{6- [(methylsulfonyl)amino]—3- phenylimidazo[1,2—b]pyridazin-2— yl}phenyl)cyc|obutyl]carbamate UPLC-MS (Method 3): RT = 1.47 min; m/z (rel intensity) 498 (90, (M+H)+), 995 (20, (M+H)+); ES- m/z (rel intensity) 496 (90, (M-H)'). tert-Butyl {1 —acetamido phenylimidazo[1,2—b]pyridazin-2— yl)pheny|]cyc|obutyl}carbamate 2012/056300 Intermediate Example Int-26: tert-Butyl (1 -{4-[6-(methylsulfonyl)phenylimidazo[1 ,2-b]pyridazinyl]- phenyl}cyclobutyl)carbamate / I HBO—IIS:O To a solution of tert-butyl (1 -{4-[6-(methy|suIfanyI)phenylimidazo[1 ,2- b]pyridaziny|]pheny|}cyc|obuty|)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-6.4 (0.10 g, 0.21 mmol) in chloroform (4 mL) was added meta-chloroperoxybenzoic acid (70% pure, 0.10 g, 0.42 mmol, 2.0 equiv) portionwise. The resulting mixture was stirred at room temperature for 12 h, then was d with DCM (10 mL). The resulting mixture was washed with an aqueous NaOH solution (2 N, 10 mL), dried (Na2804 anh.) and concentrated under reduced pressure to give tert-butyl (1 -{4- [6-(methylsu|fony|)pheny|imidazo[1,2-b]pyridazin ny|}cyc|obutyl)carbamate (0.12 g, 100%) which was used without further purification: UPLC-MS (Method 3): RT = 1.38 min; m/z (rel intensity) 519 (100, ); ES- m/z (rel intensity) 517 (10, (M-H)'). ediate Example Int-27: 1-[(tert-Butoxycarbonyl)amino]cyclobutyl}phenyl)phenylimidazo [1,2-b]pyridazinecarboxylic acid 9 J1 N o/1\CH3 H CH3 To a solution of ethyl 2—(4-{1-[(tert-butoxycarbony|)amino]cyc|obuty|}phenyI) phenylimidazo[1,2—b]pyridazinecarboxylate that was prepared in a manner analgous to that bed for Intermediate Example Int-4 (2.00 g, 3.90 mmol) in MeOH (50 mL) was added an aqueous NaOH solution (10%, 10 mL). The resulting mixture was stirred at room temperature for 24 h, then was diluted with water (100 mL). The resulting mixture was adjusted to pH 4 using an aqueous HCI solution (2 N). The resulting crystals were collected, washed with water, and dried at 40 °C to give 2—(4-{1-[(tert- butoxycarbonyl)amino]cyc|obutyl}phenyI)phenylimidazo[1,2—b]pyridazine-6— carboxylic acid (1.50 g, 79%) which was used t further purification: UPLC-MS (Method 3): RT = 0.77 min; m/z (rel intensity) 485 (100, (M+H)+), 969 (40, (2M+H)+); ES- m/z (rel intensity) 439 (60 (M-COZH)'), 483 (100, (M-H)'), 967 (20, (M-H)'). 2012/056300 Intermediate Example Int-28: Methyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)phenyl- imidazo[1 ,2-b]pyridazinecarboxylate N O+CH3 H CH3 A mixture of 2—(4-{1-[(tert-butoxycarbonyl)amino]cyc|obuty|}phenyI) phenylimidazo[1,2—b]pyridazinecarboxylic acid that was prepared in a manner analgous to that described for Intermediate e Int-27 (0.075 g, 0.16 mmol), cesium ate (0.15 g, 0.46 mmol, 3.0 equiv) and methyl iodide (0.020 mL, 0.31 mmol, 2.0 equiv) in DMF (2 mL) was stirred at room temperature for 2 days, after which additional methyl iodide (0.020 mL, 0.31 mmol, 2.0 equiv) was added and the mixture was heated at 50 °C for 3 h. The resulting mixture was treated with water (25 mL). The aqueous mixture was extracted with EtOAc (3 x 10 mL). The combined organics were dried (Na2804 anh) and concentrated under d pressure to give methyl 2—(4-{1-[(tert- butoxycarbonyl)amino]cyc|obutyl}phenyI)phenylimidazo[1,2—b]pyridazine-6— carboxylate (0.087 g, 113%) which was used without further purification: UPLC-MS (Method 3): RT = 1.46 min; m/z (rel intensity) 499 (100, (M+H)+), 997 (60, (2M+H)+).

Intermediate Example Int-29: tert-Butyl (1-{4-[6,8-bis(4-fluorophenyl)—3-phenylimidazo[1,2-b]pyridazin yl]phenyl}cyclobutyl)carbamate A mixture of tert-butyl (1-{4-[3-phenyI-6,8—dibromoimidazo[1,2-b]pyridazin yl]pheny|}cyc|obutyl)carbamate that was prepared in a manner us to that described for Intermediate e Int-6 (0.25 g, 0.42 mmol), (4- fluorophenyl)boronic acid (0.12 g, 0.84 mmol, 2.0 equiv.), 1,1'— bis(diphenylphosphino)ferrocenepalladium(I|) ride (0.034 g, 0.042 mmol, 0.1 ) and sodium carbonate (0.13 g, 1.25 mmol, 3.0 equiv) in a mixture of water (0.6 mL) and dioxane (4.5 mL) was irradiated in a microwave apparatus at 110 °C for 60 min. The resulting reaction mixture was added to water (25 mL).

The aqueous mixture was extracted with DCM (3 x 25 mL). The combined organic phases were washed with an aqueous NaOH on (2 N), dried (Na2804 anh.) and concentrated under reduced pressure to give impure tert- butyl (1-{4-[6,8-bis(4-f|uorophenyI)phenylimidazo[1,2-b]pyridazin yl]pheny|}cyc|obutyl)carbamate (0.39 g) which was used without further purification: UPLC-MS (Method 3): RT = 1.84 min; m/z (rel intensity) 629 (100, (M+H)+); ES- m/z (rel intensity) 673 (100, (M-H+HC02H)').

Intermediate Example Int-30: tert-Butyl {1 -[4-(6-{4-[methoxy(methyl)carbamoyl]phenyl}phenylimidazo [1,2-b]pyridazinyl)phenyl]cyclobutyl}carbamate 9 ji OHS N o/1\CH3 H CH3 A mixture of 2-(4-{1-[(tert-butoxycarbony|)amino]cyc|obuty|}phenyI) phenylimidazo[1,2-b]pyridazinecarboxylic acid that was prepared in a manner analgous to that described for Intermediate Example Int-27 (0.40 g, 0.82 mmol), O,N-dimethylhydroxylamine hydrochloride (0.12 g, 1.24 mmol, 1.5 equiv), PYBOP (0.54 g, 1.03 mmol, 1.25 equiv) and N,N-diisopropylethylamine (0.9 mL, 4.95 mmol, 6.0 equiv) in DMF (15 mL) was stirred at room temperature for 21 h.

The resulting mixture was added to ice water (50 mL). The aqueous mixture was extracted with EtOAc (4 x 25 mL). The combined organic phases were sequentially washed with water (25 mL) and a saturated aqueous NaCI solution (25 mL), dried (Na2804 anh.) and concentrated under reduced pressure. The resulting brown 0" (1.48 g) was purified using MPLC ge Isolera; Snap 25g dge, 100% hexane 2.0 min, gradient to 80% hexane / 20% EtOAc 1.0 min, 80% hexane / 20% EtOAc 3.0 min, gradient to 50% hexane / 50% EtOAc 6.0 min, 50% hexane / 50% EtOAc 6.5 min, gradient to 10% hexane / 90% EtOAc 6.0 min, gradient to 100% EtOAc 2.7 min, 100% EtOAc 4.5 min) to give tert- butyl {1 -[4-(6-{4-[methoxy(methyl)carbamoyl]phenyl}phenylimidazo[1 ,2- b]pyridazinyl)phenyl]cyc|obuty|}carbamate (0.25 g, 57%): UPLC-MS d 3): RT = 1.40 min; m/z (rel ity) 528 (100, (M+H)+); ES- m/z (rel intensity) 526 (10, (M-H+HC02H)'). ediate Example Int-31: utyl (1 -{4-[6-(4-acetylphenyl)phenylimidazo[1 ,2-b]pyridazinyl]- phenyl}cyclobutyl)carbamate To a solution of tert-butyl {1 -[4-(6-{4-[methoxy(methyl)carbamoyl]phenyI} phenylimidazo[1,2-b]pyridazinyl)pheny|]cyc|obuty|}carbamate that was prepared in a manner analgous to that described for Intermediate Example Int- (0.25 g, 0.47 mmol) in THF (10 mL) at 0 °C under an argon atmosphere was added methylmagnesium chloride (3 M in THF, 0.40 mL, 1.19 mmol, 2.5 equiv) portionwise h a septum. The resulting mixture was stirred at 0 °C and at room temperature for 5 h. Additional methylmagnesium chloride (3 M in THF, 0.16 mL, 0.48 mmol, 1.0 equiv) was added and the resulting mixture was stirred for 12 h. The resulting mixture was added to a saturated s ammonium chloride solution (25 mL). The aqueous mixture was extracted with EtOAc (3 x 25 mL). The ed organic phases were dried (Na2804 anh.) and concentrated under reduced pressure. The resulting yellow OH (0.23 g) was purified using MPLC (Biotage Isolera; Snap 10g cartridge, 100% hexane 2.0 min, gradient to 50% hexane / 50% EtOAc 2.0 min, 50% hexane / 50% EtOAc 2.0 min, gradient to 100% EtOAc 5.0 min, 100% EtOAc 21.0 min) to give tert- butyl (1 -(4-acety|phenyI)phenylimidazo[1 ,2-b]pyridazin yl]pheny|}cyc|obutyl)carbamate (0.053 g, 23%): UPLC-MS (Method 3): RT = 1.51 min; m/z (rel intensity) 483 (100, (M+H)+), 965 (80, (2M+H)+); ES- m/z (rel intensity) 481 (10, (M-H)').

Intermediate Example Int-32: tert-Butyl {1 -[4-(3-phenylpropylimidazo[1 ,2-b]pyridazinyl)phenyl]- cyclobutyl}carbamate To a e of tert-butyl {1 -[4-(6-ch|orocyc|opropyIphenylimidazo[1 ,2- b]pyridaziny|)phenyl]cyc|obuty|}carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-14.6 (0.136 g, 0.26 mmol) and 5% palladium on carbon (0.026 g) in DMF (1 mL) was added a solution of sodium formate (0.18 g, 2.6 mmol, 10.0 eq) in water (0.4 mL). The resulting e was stirred at 80 °C for 3 h, diluted with MeOH (10 mL) and stirred at room temperature for 1 h. The resulting solution was filtered h a membrane filter and concentrated under reduced pressure. The resulting material was purified using MPLC (Biotage Isolera; Snap 10g cartridge, 100% hexane 2.0 min, gradient to 80% hexane / 20% EtOAc 4.0 min, 80% hexane/ % EtOAc 2.5 min, nt to 70% hexane / 30% EtOAc 2.5 min, 70% hexane /30% EtOAc 9.6 min) to give tert-butyl {1 -[4-(3-phenyIpropylimidazo[1 ,2- daziny|)phenyl]cyc|obuty|}carbamate (0.12 g, 93%): UPLC-MS (Method 3): RT = 1.65 min; m/z (rel intensity) 483 (100, (M+H)+), 965 (60, (M+H)+) ; ES— m/z (rel intensity) 481 (10, (M-H)'). ediate e Int-32: tert-Butyl {1 -[4-(6-chloro-7,8-dimethylphenylimidazo[1 ,2-b]pyridazin yl)phenyl]cyclobutyl}carbamate A mixture of crude tert-butyl (1 -{4- (phenyl)acetyl]pheny|}cyc|obutyl)carbamate [that was prepared in a manner analgous to that described for Intermediate Example IntA] (237 mg, ~80% purity, 0.430 mmol, 1.0 eq), 6-ch|oro-4,5-dimethylpyridazinamine (CAS-Nr. 765937, 67.2 mg, 0.430 mmol, 1.0 eq) and N,N- diisopropylethylamine (70 uL, 0.430 mmol, 1.0 eq) in butyronitrile (2.6 mL) was heated for 17 hours at 125 °C. On cooling the mixture was partitioned between DCM and water, stirred vigorously and filtered through a silicone coated filter paper. The filtrate was concentrated in vacuo. The crude mixture was purified via MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane/EtOAc 9/1 -> /EtOAc 3/2) to give 185 mg (78% yield) of the title compound.

UPLC-MS (Method 2): RT = 1.68 min; m/z = 504 .

Intermediate Example Int-33: Methyl 6-amino-4,5-dimethylpyridazinecarboxylate H30 NH2 H3C / \N A e of 6-ch|oro-4,5-dimethylpyridazinamine (CAS—Nr.765937, 1.00 g, 6.35 mmol, 1.0 eq), [1 ,1,-bis-(diphenylphosphino)ferrocene]—palladium(|I) dichloride (1.04 g, 1.27 mmol, 0.2 eq) and triethylamine (973 uL, 6.98 mmol, 1.1 eq) was placed in 90 mL autoclave and dissolved in 11.3 mL MeOH/THF (10/1).

The autoclave was flushed with carbon monoxide (3x) and was then pressurized with carbon monoxide to 9 bar. The reaction mixture was d for 30 min at RT. The carbon monoxide was released and the autoclave was then degassed by the use of high . The autoclave was again pressurized to 9 bar with carbon monoxide and subsequently heated to 100°C. In the course of the reaction, carbon monoxide consumption was observed (decrease of CO pressure). The autoclave was cooled to rt, and after release of carbon monoxide flushed with inert gas. The reaction e was filtered through a small pad of Celite. The crude mixture was purified via MPLC (Biotage lsolera; 50 g SNAP cartridge: DCM-> DCM/ethanol 95/5) to give 1.28 g (95% yield) of the title compound in 85% purity (UPLC, area-%).

UPLC-MS (Method 2): RT = 0.62 min; m/z = 182 (M+H) t.

Intermediate Example Int-34: tert-Butyl {1 -[4-(6-methoxy-7,8-dimethylphenylimidazo[1 yridazin yl)phenyl]cyclobutyl}carbamate 9 i CHEH 3 N O CH Step 1: 6-Methoxy—4,5-dimethylpyridazinamine H30 NH 6-Chloro-4,5-dimethylpyridazinamine (CAS—Nr. 76593-36—7, 500 mg, 3.17 mmol, 1.0 eq) in 14.51 mL of a 25% solution (w/w) of sodium ate in MeOH was heated for 1 h at 130 °C in a single mode microwave oven. The reaction mixture was partitioned n DCM and water. The organic phase was washed with brine and dried (Na2804 anh.). Volatile components were 2012/056300 removed by the use of a rotary evaporator and the crude mixture was purified via MPLC ge Isolera; 25 g SNAP NH2 cartridge: hexane-> /EtOAc 1/1) to give 250 mg (49% yield) of the title compound. 1H-NMR (400 MHz, d6-DMSO): 6 [ppm] = 1.98 (s, 3H), 2.00 (s, 3H), 5.49 (s, 3H), NH2 not assigned.

Step 2: tert-Butyl {1-[4-(6-methoxy-7,8-dimethylphenylimidazo[1,2-b]- pyridazinyl)phenyl]cyclobutyl}carbamate . O CH JL J H3C / ’N/ ‘N O A mixture of crude tert-butyl (1 -{4- (phenyl)acetyl]pheny|}cyclobuty|)carbamate [that was prepared in a manner analgous to that described for Intermediate Example |ntA] (391 mg, ~80% purity, 0.710 mmol, 1.0 eq), 6-methoxy-4,5-dimethylpyridazinamine (that was prepared in a manner analgous to that described for ediate Example Int-34, Step 1, 108 mg, 0.710 mmol, 1.0 eq) and N,N- diisopropylethylamine (140 uL, 0.780 mmol, 1.1 eq) in butyronitrile (4.9 mL) was heated for 3 hours at 120 °C. On cooling the reaction mixture was concentrated in vacuo. The crude mixture was purified via MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane/EtOAc 9/1 -> hexane/EtOAc 2/3) to give 105 mg (28% yield) of the title compound.

UPLC-MS (Method 2): RT = 1.68 min; m/z = 499 (M+H)+.

Intermediate Example Int-35: tert-Butyl (1 -{4-[7,8-dimethyl(methylsulfanyl)phenylimidazo[1 ,2-b]- zinyl]phenyl}cyclobutyl)carbamate 9 i CHEH 3 N O CH H3C / N/ Step 1: methyl(methylsulfanyl)pyridazinamine H30 NH2 6-Ch|oro-4,5-dimethylpyridazinamine (CAS—Nr. 76593-36—7, 400 mg, 2.54 mmol, 1.0 eq) and sodium methanethiolate (196 mg, 2.79 mmol, 1.1 eq) in .4 mL l were heated for 1 h to 130 °C in a single mode microwave oven. The reaction mixture was partitioned between DCM and water. The organic phase was washed with brine and dried with sodium sulfate. The resulting mixture was filtered through a Whatman filter and the volatile components were removed in vacuo. The crude mixture was purified via MPLC (Biotage Isolera; 50 g SNAP cartridge: DCM/ethanol 95/5 -> hanol 4/1) to give 182 mg (21% yield) of the title compound in 50% purity (UPLC, area-%).

UPLC-MS (Method 2): RT = 0.76 min; m/z = 170 (M+H)+.

Step 2: tert-Butyl (1-{4-[7,8-dimethyl(methylsulfanyI)phenyl- imidazo[1,2-b]pyridazin-2—yl]phenyl}cyclobutyl)carbamate .0 CH3 NAka—'3o N 0 . CH3 A mixture of crude tert-butyl (1 -{4- [bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate [that was prepared in a manner analgous to that described for Intermediate Example lntA] (540 mg, ~80% purity, 0.970 mmol, 1.0 eq), 4,5-dimethyl(methylsulfanyI)-pyridazin amine (that was prepared in a manner analgous to that bed for Intermediate Example Int-35, Step 1, 181 mg, ~50% purity, 1.07 mmol, 1.1 eq) and N,N-diisopropylethylamine (170 uL, 0.970 mmol, 1.1 eq) in butyronitrile (4.7 mL) was heated for 4 hours at 125 °C. On cooling the reaction mixture was concentrated in vacuo. The crude mixture was purified via ed phase preparative HPLC to give 105 mg (19% yield) of the title compound.

UPLC-MS d 2): RT = 1.74 min; m/z = 516 (M+H)+.

Intermediate Example Int-36: tert-Butyl {1 -[4-(6-ethoxy-7,8-dimethylphenylimidazo[1 yridazin yl)phenyl]cyclobutyl}carbamate 2012/056300 Step 1: 6-Ethoxy—4,5-dimethylpyridazinamine H30 NH HC /\ ro-4,5-dimethylpyridazinamine (CAS—Nr. 76593-36—7, 500 mg, 3.17 mmol, 1.0 eq) and sodium ethanolate in ethanol (16 mL, 21 w/w-%, 53.9 mmol, 17 eq) were heated for 2 h to 130 °C in a single mode microwave oven.

The reaction mixture was partitioned between DCM and water. The organic phase was washed with brine and dried with sodium sulfate. The resulting mixture was filtered through a Whatman filter and the volatile components were removed in vacuo. The crude mixture was purified via MPLC (Biotage lsolera; 28 g NH2—cartridge: hexane -> /EtOAc 1/1) to give 267 mg (50% yield) of the title compound.

UPLC-MS (Method 2): RT = 0.78 min; m/z = 168 (M+H)+.

Step 2: tert-Butyl {1-[4-(6-ethoxy-7,8-dimethylphenylimidazo[1,2-b]- pyridazinyl)phenyl]cyclobutyl}carbamate . 0 CH3 NJLOJYCHs N O . CH3 A mixture of crude tert-butyl (1 -{4- (phenyl)acetyl]phenyl}cyclobutyl)carbamate [that was prepared in a manner analgous to that described for Intermediate Example lntA] (300 mg, ~80% purity, 0.540 mmol, 1.0 eq), 6-ethoxy-4,5—dimethylpyridazinamine (that was prepared in a manner analgous to that described for Intermediate Example lnt-36,Step 1, 124 mg, ~80% purity, 0,590 mmol, 1.1 eq) and N,N- diisopropylethylamine (100 uL, 0.590 mmol, 1.1 eq) in butyronitrile (3.3 mL) was heated for 3.5 hours at 125 °C. On cooling the reaction mixture was concentrated in vacuo. The crude e was purified via preparative MPLC (Biotage Isolera; 50 g SNAP-cartridge: /EtOAc 9/1 -> hexane/EtOAc 1/1) to give 220 mg (70% yield) of the title compound.

UPLC-MS (Method 2): RT = 1.74 min; m/z = 514 (M+H)+.

Example 1: 1-[4-(6-Methylphenylimidazo[1,2-b]pyridazinyl)phenyl]cyclobutan- amine To a mixture of tert- butyl {1 -[4-(6(- methyl---3 phenylimidazo[1, 2- b]pyridazin- yl)phenyl]-cyc|obuty|}carbamate that was prepared'In a manner analgous to that bed for Intermediate Example Int-1 (200 mg, 0.440 mmol, 1.0 eq) in DCM (2.2 mL) and methanol (1.8 mL) was added a solution of 4 M hydrogen chloride in dioxane (2.2 mL, 8.80 mmol, 20.0 eq) and the mixture was d for overnight at rt. The mixture was poured onto ice, made alkaline with aqueous sodium hydroxide (2 N) and extracted with DCM. The combined organic phases were washed with brine, dried and concentrated in vacuo. Purification was achieved by crystallization from diisopropyl ether. The resulting solid was filtered and dried under high vacuum overnight to give 130 mg (83% yield) of the title compound.

UPLC-MS (Method 2): RT = 1.20 min; m/z = 355.68 (M+H). 1H-NMR (400 MHz, MeOD): 6 [ppm] = 1.96 (m, 1H), 2.24 (m, 1H), 2.54-2.64 (m 2H), 2.67 (s, 3H), .84 (m, 2H), 7.49 - 7.65 (m, 7H), 7.66 - 7.71 (m, 2H), 7.80 (d, 1H), 8.32 (d, 1H), Nflz not assigned. e 2: 1-[4-(6-Ethylphenylimidazo[1,2-b]pyridazinyl)phenyl]cyclobutanamine To a mixture of utyl {1-[4-(6—ethylphenylimidazo[1,2-b]pyridazin yl)phenyl]cyclobutyl}carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-2 (300 mg, 0.608 mmol, 1.0 eq) in DCM (3.9 mL) and MeOH (2.5 mL) was added a solution of 4 M hydrogen chloride in dioxane (3.0 mL, 12.2 mmol, 20.0 eq) and the mixture was stirred for ght at rt. The mixture was poured onto ice, made alkaline with aqueous sodium hydroxide (2 N) and extracted with DCM. The combined organic phases were washed with brine, dried and trated in vacuo. Purification was achieved by crystallization from diisopropyl ether. The resulting solid was filtered and dried under high vacuum overnight to give 119 mg (52% yield) of the title UPLC-MS (Method 4): RT = 1.37 min; m/z = 369.29 (M+H). 1H-NMR (400 MHz, d6-DMSO): 6 [ppm] = 1.18 (t, 3H), 1.59 (m, 1H), 1.82-2.20 (m, 5H), 2.25-2.39 (m, 2H), 2.73 (q, 2H), 7.20 (d, 1H), 7.31 - 7.38 (m, 2H), 7.39 - 7.56 (m, 7H), 8.06 (d, 1H).

Example 3: 1-{4-[3-Phenyl(trifluoromethyl)imidazo[1,2-b]pyridazinyl]phenyl}- cyclobutanamine F F To a mixture of utyl (1 -{4-[3-phenyl(trifluoromethyl)imidazo[1 ,2- b]pyridaziny|]phenyl}cyclobutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-3 (680 mg, 1.177 mmol, 1.0 eq) in DCM (7.6 mL) and methanol (4.8 mL) was added a solution of 4 M hydrogen chloride in dioxane (5.9 mL, 23.5 mmol, 20.0 eq) and the mixture was stirred for overnight at rt. The e was poured onto ice, made alkaline with aqueous sodium hydroxide (2 N) and extracted with EtOAc (3x). The combined organic phases were washed with brine, dried and concentrated in vacuo.

Purification was achieved by crystallization from diisopropyl ether. The resulting solid was filtered and dried under high vacuum overnight to give 440 mg (92% yield) of the title nd.

S (Method 4): RT = 1.40 min; m/z = 393.58 (M-NH2)+. 1H-NMR (400 MHz, d6-DMSO): 6 [ppm] = 1.60 (m, 1H), 1.85-2.25 (m, 5H), .39 (m, 2H), 7.40 (d, 2H), 7.45 - 7.61 (m, 7H), 7.67 (d, 1H), 8.46 (d, 1H).

Example 4: Ethyl 2-[4-(1-aminocyclobutyl)phenyl]phenylimidazo[1,2-b]pyridazine—6- carboxylate H304 0 To a mixture of ethyl 2—(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl) phenylimidazo[1,2-b]pyridazinecarboxylate that was ed in a manner analgous to that described for Intermediate Example Int-4 (0.96 g, 1.87 mmol) in DCM (12.0 mL) and methanol (7.6 mL) was added a solution of 4 M hydrochloric acid in dioxane (9.4 mL) and the mixture was stirred for 2 hours at rt. The mixture was poured onto ice, made alkaline with aqueous sodium ide (2 N) and extracted with DCM. The combined organic phases were washed with brine, dried and trated in vacuo. The reaction was repeated using 2.5 g of the carbamate and the crude product from both reactions were combined. Purification was achieved by chromatography on silica (gradient elution: 95:5 DCM:ethanol to 8:2 DCM:ethano|) to give two fractions of the title compound (0.8 g, 88% purity & 1.6 g, 93% purity).

UPLC-MS (Method 3): RT = 0.97 min; m/z = 413.44 (M+H).

Example 5: 2-[4-(1-Aminocyclobutyl)phenyl]phenylimidazo[1,2-b]pyridazine—6- carboxamide A mixture of ethyl 2-[4-(1-aminocyclobuty|)pheny|]pheny|imidazo[1,2- b]pyridazinecarboxylate that was prepared in a manner analgous to that described for e 4, (1.00 g, 93% purity) and ammonia (17.3 mL of a 7M on in methanol) was heated at 130 °C under microwave irradiation for 5 hours. The volatile components were removed by distillation under reduced re. llization from methanol/diisopropyl ether gave the title compound (672 mg, 72% yield) as a yellow solid.

UPLC-MS (Method 2): RT = 0.99 min; m/z = 366.59 (M-NH2). 1H-NMR (400 MHz, d6-DMSO): 5 [ppm] = 8.26 (d, 1H), 7.87 (br s, 1H), 7.69 (d, 1H), 7.61 - 7.63 (m, 2H), 7.55 - 7.57 (m, 3H), 7.44 - 7.53 (m, 3H), 7.39 (d, 2H), 2.29 - 2.36 (m, 2H), 1.89 - 2.06 (m, 5H), 1.55 - 1.65 (m, 1H).

Example 6: 1-[4-(6-Methyloxyphenylimidazo[1,2-b]pyridazinyl)phenyl]cyclobutan- amine To a mixture of tert- buty|((1-{ [3- phenyl-methoxyimidazo[1, 2- b]pyridazin- yl]pheny|}cyc|obutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-5 (550 mg, 1.17 mmol) in DCM (7.5 mL) and MeOH (0.8 mL) was added a 4 M hydrogen chloride solution in dioxane (5.8 mL, 23.4 mmol, 20.0 eq), and the resulting mixture was stirred at room temperature for 12 h. The resulting mixture was added to ice water, made alkaline with aqueous sodium hydroxide (2 N), and extracted with EtOAc (3 x 25 mL). The combined organic phases were , dried (Na2804 anh.) and concentrated under reduced pressure. The resulting material was ed using MPLC (Biotage lsolera; 100 g SNAP cartridge: 100% DCM 3.5 min., gradient to 95% DCM /5% MeOH 1 min., 95% DCM /5% MeOH 3.5 min., gradient to 90% DCM /10% MeOH 1 min., 90% DCM /10% MeOH 4.5 min.) to give 1-[4-(6- methyloxyphenylimidazo[1,2-b]pyridazinyl)phenyl]cyclobutanamine (379 mg, 83% yield): UPLC-MS (Method 3): RT = 1.28 min; m/z (rel intensity) 371 (95, (M+H)+). 1H-NMR (DMSO-d6): 5 [ppm] 1 .-52 1.66 (m, 1H), 1.87-2.08 (m, 3H), 2.05-2.28 (br m, 2H), 2.28-2.38 (m, 2 H), 3.79 (s, 3H), 6.91 (d, J=9.6 Hz, 1H), 7.35 (d, J=8.7 Hz, 2H), 7.40-7.53 (m, 3H), 7.49 (d, 8.5 Hz, 2H), 7.57 (ddm, J=8.3, 1.5 Hz, 2H), 8.05 (d, J=9.6 Hz).

Example 7: 1-[4-(6-Bromomethyloxyphenylimidazo[1,2-b]pyridazinyl)phenyl]- cyclobutanamine To a solution of tert-butyl((1-{[3-phenyl---6bromo-methoxyimidazo[1, 2- b]pyridazinyl]phenyl}cyclobutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-7 (100 mg, 0.18 mmol) in dioxane (4 mL) was added oromethanesulfonic acid (0.61 mL, 1.8 mmol, 10.0 eq), and the resulting mixture was stirred at room ature for 12 h.

The resulting mixture was added to ice water, made alkaline with aqueous sodium hydroxide (2 N), and extracted with EtOAc (3 x 25 mL). The combined organic phases were washed, dried (Na2804 anh.) and trated under reduced pressure. The ing al was purified using MPLC (Biotage |so|era; SNAP 10g cartridge: 100% DCM 4.0 min., gradient to 95% DCM /5% MeOH 1 min., 95% DCM /5% MeOH 3.5 min., gradient to 90% DCM /10% MeOH 1 min., 90% DCM /10% MeOH 3.5 min., gradient to 80% DCM /20% MeOH 6 min., 80% DCM /20% MeOH 4.7 min.) to give material (40 mg) which was further purified by preparative HPLC (Waters rification System equipped with pump 254, Sample r 2767, CFO, DAD 2996, ELSD 2424 and SQD 3001 using a t CSH C18 5 uM 100x30 mm column; 60% water with 1% HCOzH /40% methanol 1 min., gradient to 10% water with 1% HCOzH / 90% methanol 7 min) to give 1-[4-(6-bromomethyloxyphenylimidazo[1,2- b]pyridazinyl)phenyl]cyclobutanamine (15 mg, 18%): UPLC-MS (Method 3): RT = 1.32 min; m/z (rel intensity) 432 (95, (M+H-17)+), 449 (60, ). 1H-NMR (DMSO-ds): 6 [ppm] 1.55-1.65 (m, 1H), .00 (m, 1H), .11 (m, 2H), 2.30-2.38 (m, 2H), 4.10 (s, 3H), 7.03 (s, 1H), 7.36 (d, J=8.6 Hz, 2H), 7.45-7.54 (m, 7H).

Example 8: 2-[4-(1-Aminocyclobutyl)phenyl]phenylimidazo[1,2-b]pyridazine—6- carboxylic acid To a solution of ethyl 2-[4-(1-aminocyclobutyl)pheny|]pheny|imidazo[1,2- b]pyridazinecarboxylate that was prepared in a manner analgous to that described for Example 4 (260 mg, 0.63 mmol) in methanol (1.5 mL) was added aqueous sodium hydroxide (3N, 0.63 mL, 1.89 mmol, 3.0 eq), and the resulting mixture was stirred at 50°C for 1 h. The resulting mixture was added to ice water, made slightly acidic with aqueous citric acid (10%), and washed with DCM (3 x 25 mL). The aqueous phase was made alkaline and adjusted to pH4 using hydrochloric acid (1 N). The precipitate was collected by filtration, washed with water and dried under high vacuum overnight to yield 218 mg (88% yield) of the title compound.

UPLC-MS (Method 1): RT = 0.71 min; m/z (ESneg) = 383 (M-H)‘. 1H-NMR (DMSO-ds, + 1 drop TFA-d): 6 [ppm] 1.77 (m, 1H), 1.10 (m, 1H), 2.40- 2.64 (m, 4H, lly obscured by solvent signal), 7.40-7.60 (d, 7H), 7.68 (d, 2H), 7.78 (d, 1H), 8.30 (d, 1H), 8.50 (m, 1H).

Example 9: 1-[4-(6,8-Dimethyloxy—3-phenylimidazo[1,2-b]pyridazinyl)phenyl]- cyclobutanamine To a solution of tert-butyl((1-{[3-phenyl--6, 8--dimethoxyimidazo[1, 2- b]pyridazin- 2-yl]phenyl}cyclobutyl)carbamate that was prepared in a manner analgous to that described for Intermediate e Int-7 (0.18 g, 0.37 mmol) in methanol (2.2 mL) and DCM (3.5 mL) was added hydrogen chloride (4 M in dioxane, 1.8 mL, 7.3 mmol, 20.0 eq), and the resulting mixture was stirred at room ature for 20 h. The resulting mixture was added to ice water, made alkaline with aqueous sodium hydroxide (2 N), and ted with EtOAc (3 x 25 mL). The combined organic phases were dried (Na2804) and concentrated under reduced pressure. The resulting material was purified using MPLC (Biotage lsolera; 10 g SNAP cartridge: 100% DCM 6.0 min., gradient to 95% DCM /5% MeOH 4 min., 95% DCM /5% MeOH 5 min., gradient to 90% DCM /10% MeOH 3.5 min.) to give 1-[4-(6,8-dimethyloxyphenylimidazo[1,2- b]pyridazinyl)phenyl]cyclobutanamine (0.11 g, 79%): UPLC-MS (Method 3): RT = 1.31 min; m/z (rel ity) 384 (100, 7)+), 401 (70, (M+H)+). 1H-NMR (DMSO-d6): 6 [ppm] 1.-52 1.65 (m, 1H), 1.88-2.07 (m, 5H), 2.27-2.38 (m, 2H), 3.77 (s, 3H), 4.03 (s, 3H), 6.40 (s, 1H), 7.34 (d, J=8.5 Hz, 2H), 7.39- 7.50 (m, 5H), 7.51-7.56 (m, 2H).

WO 36776 Example 10: 2-[4-(1-Aminocyclobutyl)phenyl]methoxyphenylimidazo[1,2-b]- pyridazine—6-carboxamide To a solution of 2-(4-{1-[(tert-butoxycarbony|)amino]cyc|obuty|}pheny|) methoxyphenylimidazo[1,2-b]pyridazinecarboxylamide that was prepared in a manner analgous to that described for Intermediate Example Int-10 (0.095 g, 0.18 mmol) in MeOH (1 mL) and DCM (1.8 mL) was added en chloride (4 M in dioxane, 0.9 mL, 3.7 mmol, 20.0 eq), and the resulting mixture was stirred at room temperature for 3 days. The resulting mixture was added to ice water, made alkaline with s sodium hydroxide (2 N), and extracted with EtOAc (3 x 50 mL). The combined organic phases were dried (Na2804 anh.) and concentrated under reduced pressure. The resulting material was purified using preparative HPLC (Waters Autopurification System equipped with pump 254, Sample Manager 2767, CFO, DAD 2996, ELSD 2424 and SQD 3001 using a Xselect CSH C18 5 uM 100x30 mm column; 60% water with 1% HCOzH / 40% MeOH 1 min., gradient to 10% water with 1% HCOzH / 90% MeOH 7 min) to give 1-aminocyc|obuty|)pheny|]methoxypheny|imidazo[1,2- b]pyridazinecarboxamide (0.020 g, 31%): UPLC-MS (Method 3): RT = 1.03 min; m/z (rel intensity) 397 (100, (M+H-17)+), 414 (50, (M+H)+); ES— m/z (rel intensity) 412 (70, (M-H)'). 1H-NMR (DMSO-de): 6 [ppm] 1.53-1.66 (m, 1H), 1.89-2.07 (m, 5H), 2.12 (br s, 2H). 2.28-2.38 (m, 2H), 4.07 (s, 3H), 7.15 (s, 1H), 7.37 (d, J=8.5 Hz, 2H), 7.42- 7.56 (m, 6H), 7.56-7.62 (m, 2H), 7.82 (br s, 1H).

Example 11 : 1-[4-(8-Methoxyphenylimidazo[1,2-b]pyridazinyl)phenyl]cyclo- butanamine To a solution of tert-butyl {1 -[4-(8-methoxyphenylimidazo[1 ,2-b]pyridazin yl)pheny|]cyc|obuty|}carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-11 (0.055g, 0.12 mmol) in a mixture of MeOH (0.7 mL) and DCM (1.1 mL) was added a concentrated aqueous HCI solution (approximately 12 N, 0.6 mL). The resulting mixture was stirred at room temperature for 60 h, then poured onto ice water (15 mL). The resulting mixture was made basic with a 2 N NaOH solution, then was extracted with EtOAc (3 x mL). The combined organic phases were dried (Na2804 anh.) and concentrated under reduced pressure. The resulting oil (34 mg) was purified using preparative HPLC (Agilent Prep 1200 equipped with 2 x Prep Pump, DLA, MWD, ELSD and Prep FC using an XBrigde C18 5um 100x30 mm column; gradient from 70% water with 0.2% NH3 / 30% CH3CN to 40% water with 0.2% NH3 / 60% CH3CN over 17.5 min, nt from 40% water with 0.2% NHs / 60% CH3CN to 100% CH3CN over 2.5 min) to give 1-[4-(8—methoxy phenylimidazo[1,2-b]pyridazinyl)pheny|]cyc|obutanamine (0.021 g, 48% yield): UPLC-MS (Method 3): RT = 1.18 min; m/z (rel intensity) 371 (30, (M+H)+). 1H-NMR (DMSO-de): 6 [ppm] 1.52-1.65 (m, 1H), 1.87-2.13 (m, 5H), 2.12 (br s, 2H). .37 (m, 2H), 4.06 (s, 3H), 6.73 (d, J=5.7 Hz 1H), 7.35 (d, J=8.7 Hz, 2H), .50 (m, 5H), 7.53, (d, J=8.7 Hz, 2H).

The following examples were prepared in a manner analogous to Example 11 by reacting the corresponding ate intermediates with a concentrated aqueous HCI solution Example Structure/ Name Characterization 12 UPLC-MS (Method 3): RT = 1.21 min; m/z (rel intensity) 429 (70, (M+H)+). 1H-NMR (DMSO-d6): 6 [ppm] 1.55-1.64 (m, 1H), 1.89-2.05 Methyl 2-[4-(1- (m, 4H), 2.12 (br s, 2H). 2.30- aminocyclobuty|)pheny|] 2.36 (m, 2H), 3.85 (s, 3H), 4.15 methoxyphenylimidazo[1,2- (s, 3H), 7.18 (s, 1H), 7.36 (d, b]pyridazinecarboxylate J=8_6 Hz, 2H), 7.46-7.55 (m 7H). 13 UPLC-MS (Method 3): RT = ; 1.34 min; m/z (rel intensity) 399 (50, ). 1H-NMR (DMSO-d6): 6 [ppm] 1.19 (t, J=7.5 Hz, 3H), 1.53- 1--[4-6(- Ethyl--m-ethoxy3-- 1.65 (m, 1H), 1.87-2.10 (m phenylimidazo[1,2-b]pyridazin- 5H), 2.27-2.37 (m, 2H), 2.68 (q, 2-yl)pheny|]cyc|obutanamine J=7.5 Hz, 2H), 4.05 (s, 3H), 6.70 (s, 1H), 7.34 (d, J=8.5 Hz, 2H), 7.42-7.52 (m, 7H). 14 S (Method 3): RT = 1.41 min; m/z (rel ity) 431 (100, (M+H-17)+), 448 (70, (M+H)+). 1H-NMR (DMSO-d6): 6 [ppm] 1-{4-[6-Methoxyphenyl'8' 1.55-1.65 (m, 1H), 1.87-2.20 (pyridinyl)imidazo[1,2- (m, 5H), 2.29-2.39 (m, 2H), b]pyridazin 3.85 (s, 3H), 7.35 (s, 1H), 7.38 yl]phenyl}cyclobutanamine (d, J=8.5 Hz, 2H), .54 (m 5H), 7.58-7.63 (m, 3H), 8.70- 8.77 (m, 2H), 9.50 (dm, J=2.2 Hz, 1H).

Example Structure/ Name Characterization UPLC-MS (Method 3): RT = 1.34 min; m/z (rel intensity) 420 (100, (M+H-17)+), 437 (50, (M+H)+). 1H-NMR (DMSO-de): 6 [ppm] 1-{4-[6-MethoxyphenyI 1.56-1.64 (m, 1H), 1.89-2.12 (1 H-pyrazoIyl)imidazo[1 ,2- (m, 4H), .38 (m, 3H), b]pyridazin 3.78 (s, 3H), 7.23 (s, 1H), 7.36- Y']phenyl}cyclobutanamine 7.41 (m, 3H), .50 (m, HCI salt 4H), 7.54-7.62 (m, 4H), 9.22 (s, 1H), 8.60-8.93 (br m, 2H). 16 UPLC-MS (Method 3): RT = 1.52 min; m/z (rel intensity) 380 (90, (M+H-17)+), 397 (100, (M+H)+). 1H-NMR (CD30D): 6 [ppm] 1-[4-(6,8—DiethyI 1.33 (t, J=7.6 Hz, 3H), 1.47 (t, phenylimidazo[1,2-b]pyridazin- J=7.6 Hz, 3H), .82 (m, 2-yl)phenyl]cyclobutanamine 1H), 2.06-2.15 (m, 2H), 2.24- 2.32 (m, 2H), 2.57-2.63 (m, 2H), 2.85 (q, J=7.6 Hz, 2H), 3.14 (qd, J=7.6, 1.0 Hz, 2H), 7.08 (s, 1H), 7.42-7.49 (m, 5H), 7.55 (dd, J=7.9, 1.3 Hz), 7.61 (d, J=8.5 Hz, 2 H).

Example 17: 1-[4-(6-Chlorophenylimidazo[1,2-b]pyridazinyl)phenyl]cyclobutan- amine To a solution of tert-butyl {1- [4-(6(-chloro phenylimidazo[1, 2-b—]pyridazin- yl)pheny|]cyc|obutyl}carbamate that was prepared in a manner us to that described for Intermediate Example Int-6.2 (0.075 g, 0.15 mmol) in MeOH (0.65 mL) and DCM (1.0 mL) was added hydrogen chloride (4 M in dioxane, 0.8 mL, 3.2 mmol, 20.0 eq), and the resulting mixture was d at room temperature for 19 h. The resulting e was added to ice water (50 mL), made alkaline with aqueous sodium hydroxide (2 N), and extracted with EtOAc (2 x 50 mL).

The combined organic phases were dried (Na2804 anh.) and concentrated under reduced pressure. The resulting material was recrystallized using diisopropyl ether to give 1-[4-(6-chlorophenylimidazo[1,2-b]pyridazin nyl]cyc|obutanamine (0.040 g, 68%): UPLC-MS (Method 3): RT = 1.32 min; m/z (rel intensity) 358 (100, (M+H-17)+), 375 (60, (M+H)+). 1H-NMR (DMSO-d6): 6 [ppm] 1.-52 1.65 (m, 1H), 1.87-2.07 (m, 3H), 2.16 (brs, 2H). .37 (m, 2H), 7.35-7.40 (m, 3H), 7.48-7.56 (m, 7H), 8.25 (d, J=9.4 Hz, 1H).

Example 18: 1-[4-(8-Methoxyphenylvinylimidazo[1,2-b]pyridazinyl)phenyl]- cyclobutanamine To a solution of utyl {1 -methoxyphenylvinylimidazo[1 ,2- b]pyridazinyl)phenyl]cyclobutyl}carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-12 (40 mg, 0.081 mmol) in dioxane (1.7 mL) was added trifluoromethanesulfonic acid (0.61 mL, 1.8 mmol, 10.0 eq), and the ing mixture was stirred at room temperature for 12 h. The resulting mixture was added to ice water, made alkaline with aqueous sodium hydroxide (2 N), and extracted with EtOAc (3 x 25 mL). The combined c phases were washed, dried (Na2804 anh.) and concentrated under reduced pressure. The resulting material was purified using MPLC (Biotage lsolera; 10 g SNAP cartridge: 100% DCM 3.0 min., gradient to 95% DCM /5% MeOH 1 min., 95% DCM /5% MeOH 2.5 min., gradient to 90% DCM /10% MeOH 3 min., 90% DCM /10% MeOH 3.5 min.) to give 1-[4-(8-methoxy phenylvinylimidazo[1,2-b]pyridazinyl)phenyl]cyclobutanamine (0.022 g, 70%): UPLC-MS (Method 3): RT = 1.32 min; m/z (rel intensity) 380 (95, (M+H-17)+), 397 (70, (M+H)+). 1H-NMR (DMSO-de): 5 [ppm] 1.54-1.64 (m, 1H), 1.89-2.10 (m, 5H), 2.28-2.36 (m, 2H), 4.11 (s, 3H), 5.63 (d, J=11.4 Hz, 1H), 6.27 (d, J=17.7 Hz, 1H), 6.64 (dd, J=17.7, 11.1 Hz, 1H), 7.06 (s, 1H), 7.35 (d, J=8.3 Hz, 2H), 7.42-7.53 (m, 8H).

The following examples were prepared in a manner analogous to e 18 by ng the corresponding carbamate intermediates with trifluoromethanesulfonic acid Structure/ Name Characterization UPLC-MS (Method 3): RT = 1.39 min; m/z (rel intensity) 424 (90 (M+H-17)+), 441 (100, (M+H)+); ES— m/z (rel intensity) 438 (100, (M-H)'). 1-{4-[6-Ch|oropheny|(1 H- 1H-NMR (DMSO-de): 6 [ppm] pyrazoIyl)imidazo[1,2- 1.55-1.66 (m, 1H), 1.90-1.99 b]pyridazin-2— (m, 1H), 2.00-2.09 (m, 2H), y|]pheny|}cyclobutanamine 2.31-2.39 (m, 2H), 7.41 (d, J=8.3 Hz, 2H), 7.49-7.56 (m, 5H), 7.62 (d, J=8.3 Hz, 2H), 7.74-7.76 (m, 2H), 7.97 (d, J=2 Hz, 1H).

UPLC-MS (Method 3): RT = 1.39 min; m/z (rel intensity) 416 (90 (M+H-17)+), 433 (100, (M+H)+), 865 (10 +); ES- m/z (rel intensity) 431 (100, (M- 1-{4-[3-PhenyI(1H-pyrazol- H)'). 6-viny|imidazo[1,2- 1H-NMR de): 6 [ppm] b]pyridazin-2— 1.53-1.67 (m, 1H), 1.88-2.21 y|]pheny|}cyclobutanamine (m, 5H), 2.29-2.39 (m, 3H), .66 (d, J=11.1 Hz, 1H), 6.24 (d, J=17.7 Hz, 1H), 6.76 (dd, J=17.7,11.1 Hz, 1H), 7.39 (d, J=8.3 Hz, 2H), 7.47-7.57 (m, 5H), 7.63 (d, J=8.5 Hz, 2H), 7.72 (d, J=1.5 Hz, 1H), 7.93 (br s, 1H), 8.03 (s, 1H).

WO 36776 Example Structure/ Name Characterization 21 UPLC-MS (Method 3): RT = 1.42 min; m/z (rel intensity) 418 (90 (M+H-17)+), 435 (100, (M+H)+), 891 (10 (2M+Na)+); ES— m/z (rel intensity) 433 (100, 1-{4-[6-EthylphenyI(1H- (M-H)')- pyrazoIyl)imidazo[1,2- 1H-NMR (DMSO-de): 6 [ppm] b]pyridazin 1.23 (t, J=7.6 Hz, 3H), 1.55- y|]pheny|}cyclobutanamine 1.65 (m, 1H), 1.88-1.98 (m, 1H), 2.00-2.20 (m, 3H), 2.31- 2.38 (m, 2H), 2.79 (q, J=7.6 Hz, 2H), 7.39 (d, J=8.3 Hz, 2H), 7.43-7.57 (m, 5H), 7.68 (s, 1H), 7.69 (brs, 1H)), 7.91 (brs, 1H). 22 UPLC-MS (Method 3): RT = 1.17 min; m/z (rel intensity) 425 (100 (M+H-17)+), 442 (70, (M+H)+), 883 (30 +); ES- m/z (rel intensity) 440 (60, (M- 2-[4-(1- H)').

Aminocyclobutyl)phenyl]—8- 1H-NMR (DMSO-de): 6 [ppm] ethoxy-N-methyI 1.47 (t, J=7.1 Hz, 3H), 1.55- phenylimidazo[1,2- 1.65 (m, 1H), 1.89-2.06 (m, dazinecarboxamide 6H), 2.28-2.37 (m, 2H), 2.77 (d, J=4.6 Hz, 3H), 4.45 (q, J=7.1 Hz, 2H), 7.10 (s, 1H), 7.37 (d, J=8.3 Hz, 2H), 7.43-7.53 (m, 6H), 7.55-7.59 (m, 2H), 8.09 (q, J=4.8 Hz, 1H).

Example Structure/ Name Characterization 23 UPLC-MS d 3): RT = 1.39 min; m/z (rel intensity) 438 (100 (M+H-17)+), 455 (40, (M+H)+). 1H-NMR (DMSO-de): 6 [ppm] 1-{4-[6-Chloro(1-methyl-1H- 1.70-1.82 (m, 1H), .14 pyrazolyl) (m, 1H), 2.51-2.59 (m, 2H, phenylimidazo[1,2-b]pyridazin- partially obscured by solvent 2-y|]pheny|}cyc|obutanamine signal), 4.06 (s, 3H), 7.01 (d, J=2.0 Hz, 1H), 7.46 (d, J=8.3 Hz, 2H), 7.51-7.57 (m, 5H), 7.58 (s, 1H), 7.64-7.68 (m, 3H). 24 UPLC-MS (Method 3): RT = 1.33 min; m/z (rel ity) 424 (100 (M+H-17)+), 441 (70, (M+H)+), 881 (20, (M+H)+). 1H-NMR (DMSO-de): 6 [ppm] 1-{4-[6—Chloro(1H-imidazol- 1.54-1.66 (m, 1H), 1.86-2.09 2-yl)phenylimidazo[1,2- (m, 3H), 2.29-2.39 (m, 2H), b]pyridazin 4.06 (s, 3H), 7.28 (s, 1H), 7.41 yl]phenyl}cyclobutanamine (d, J=8.5 Hz, 2H), 7.50-7.57 (m, 4H), 7.60 (d, J=8.5 Hz, 2H), 7.93 (s, 1H), 8.51 (t, J=1.4 Hz, 1H), 9.29 (s, 1H).

Example Structure/ Name Characterization qg’ UPLC-MS (Method 3): RT = 1.06 min; m/z (rel intensity) 324 (100 (M+H-17)+), 341 (40, (M+H)+); ES— m/z (rel intensity) 339 (100, (M-H)'). 1--[-4(3(- Phenylimidazo[1, 2- 11 NMR (DMSO-d6): 6 [ppm] b]pyridazin 1.55-1.67 (m, 1H), .09 y|)pheny|]cyclobutanamine (m, 3H), 2.29-2.39 (m, 2H), 4.06 (s, 3H), 7.25 (dd, J=9.2, 4.3 Hz, 1H), 7.37 (d, J=8.5 Hz, 2H), 7.43-7.52 (m, 5H), 7.57 (d, J=8.5 Hz, 2H), 8.16 (dd, J=9.2, 1.5 Hz, 1H), 8.43 (dd, J=4.5, 1.7 Hz, 1H). 26 UPLC-MS (Method 3): RT = 1.15 min; m/z (rel intensity) 411 (80 (M+H-17)+), 427 (60, (M+H)+), 853 (70, (2M+H)+); ES— m/z (rel intensity) 425 (40, 2-[4-(1- (M-H)').

Aminocyclobutyl)phenyl]—8- 1H-NMR (DMSO-de): 6 [ppm] methoxy-N-methyI 1.55-1.65 (m, 1H), .10 phenylimidazo[1,2- (m, 5H), 2.28-2.37 (m, 2H), dazinecarboxamide 2.77 (d, J=4.8 Hz, 3H), 4.34 (s, 3H), 7.13 (s, 1H), 7.37 (d, J=8.3 Hz, 2H), 7.46-7.53 (m, 5H), 7.58 (dm, J=8.3 Hz, 2H), 8.10 (q, J=4.8 Hz, 1H).

Example Structure/ Name Characterization 27 UPLC-MS (Method 3): RT = 1.25 min; m/z (rel intensity) 390 (100 (M+H-17)+), 407 (80, (M+H)+), 813 (10, (2M+H)+); ES— m/z (rel intensity) 405 (100, 1-{4-[3-PhenyI(1H-pyrazol- (M-H)'), 811 (10, (2M-H)'). 3-y|)imidazo[1 ,2—b]pyridazin-2— 1H-NMR (DMSO-de): 6 [ppm] y|]pheny|}cyclobutanamine 1.54-1.67 (m, 1H), 1.87-2.17 (m, 5H), 2.29-2.38 (m, 2H), 7.40 (d, J=8.1 Hz, 2H), 7.46- 7.57 (m, 5H), 7.64 (d, J=8.1 Hz, 2H), 7.70-7.75 (m, 2H), 7.93, br s, 1H), 8.46 (d, J=4.7 Hz, 1H). 28 UPLC-MS (Method 3): RT = 1.07 min; m/z (rel intensity) 441 (90 (M+H-17)+), 458 (100, ), 915 (30, (2M+H)+); ES— m/z (rel intensity) 456 (100, 2—[4-(1 - (M-H)'), 913 (10, (2M-H)').

Aminocyclobutyl)phenyl]—8-(2— 1H-NMR (DMSO-de): 6 [ppm] yethoxy) 1.56-1.68 (m, 1H), 1.88-2.10 phenylimidazo[1,2— (m, 4H), 2.29-2.39 (m, 3H), dazinecarboxamide 3.34 (s, 3H), 3.77-3.82 (m, 2H), 4.51-4.56 (m, 2H), 7.16 (s, 1H), 7.38 (d, J=8.5 Hz, 2H), 7.43- 7.61 (m, 9H), 7.82 (br s, 1H).

Example Structure/ Name Characterization 29 wfUPLC-MS (Method 3): RT = 1.52 min; m/z (rel intensity) 464 (100 (M+H-17)+), 481 (80, (M+H)+), 961 (50, (2M+H)+). 11 NMR (DMSO-d6): 6 [ppm] 1-{ [8—(Benzyloxy-)--6chloro—3- 1.55-1.66 (m, 1H), 1.89-1.98 phenylimidazo[1,2—b]pyridazin- (m, 1H), 2.00-2.08 (m, 2H), henyl}cyclobutanamine 2.28-2.36 (m, 2H), 5.48 (s, 2H), 7.08 (s, 1H), 7.34 (d, J=8.6 Hz, 2H), 7.40-7.56 (m, 13H). 54* UPLC-MS (Method 3): RT = 1.39 min; m/z (rel ity) 402 (100 (M+H-17)+), 419 (80, (M+H)+), 837 (10 (2M+H)+). 11 NMR (DMSO-d6): 6 [ppm] 1--[4-((6-Chloro—8---ethoxy3-- 1.46 (t, J=7.0 Hz, 3H), 1.54- phenylimidazo[1,2—b]pyridazin- 1.65 (m, 1H), 1.87-2.07 (m 2—yl)phenyl]cyclobutanamine 5H), 2.27-2.36 (m, 2H), 4.43 (q, J=7.2 Hz, 2H), 6.93 (s, 1H), 7.35 (d, J=8.5 Hz, 2H), 7.44- 7.54 (m, 7H).

W0 2012/136776 Example Structure/ Name Characterization 31 «4 UPLC-MS (Method 3): RT = 1.22 min; m/z (rel intensity) 382 (80 (M+H-17)+), 399 (100, (M+H)+). 1H-NMR d6): 6 [ppm] Methyl 2--[-4((1- 1.55-1.68 (m, 1H), 1.86-2.10 aminocyclobutyl)phenyI] (m, 3H), 2.29-2.40 (m, 2H), phenylimidazo[1,2- 3.98 (s, 3H), 7.39 (d, J=8.7 Hz, b]pyridazinecarboxylate 2H), 7.48-7.53 (m, 5H), 7.57 (d, J=8.5 Hz, 2H), 7.64 (d, J=4.5 Hz, 1H), 8.58 (d, J=4.5 Hz, 1H).

UPLC-MS (Method 3): RT = 0.69 min; m/z (rel intensity) 340 (70 (M+H-17)+), 357 (100, (M+H)+), 713 (20, ); ES- m/z (rel intensity) 355 (80, (M- H)'). yclobutyl)phenyl]—3- 1H-NMR (DMSO-d6): 6 [ppm] phenylimidazo[1,2-b]pyridazin- 1.67-1.81 (m, 1H), 2.03-2.19 8-ol (m, 1H), peak obscured by solvent signal, 5.84 (d, J=5.8 Hz, 1H), 7.32 (d, J=8.5 Hz, 2H), 7.35-7.50 (m, 7H), 7.74 (d, J=5.8 Hz, 1H).

W0 2012/136776 Example Structure/ Name Characterization 33 UPLC-MS (Method 3): RT = 1.05 min; m/z (rel ity) 418 (40 7)+), 435 (20, (M+H)+); ES— m/z (rel intensity) 479 (80, (M-H+HC02H)'). 1H-NMR (DMSO-de): 6 [ppm] 1-{4-[6-(4-Fluorophenyl) .69 (m, 1H), 1.86-2.12 phenylimidazo[1,2-b]pyridazin- (m, 3H), 22.41 (m, 2H), 2-y|]pheny|}cyc|obutanamine 5.84 (d, J=5.8 Hz, 1H), 7.34 (t, J=8.9 Hz, 2H), 7.39 (d, J=8.5 Hz, 2H), 7.45-7.63 (m, 7H), 7.85 (d, J=9.4 Hz, 1H), 8.01 (dd, J=8.9, 5.5 Hz, 2H), 8.25 (d, 9.4 Hz, 1H).

UPLC-MS (Method 3): RT = 1.03 min; m/z (rel intensity) 410 (90 (M+H-17)+), 427 (100, (M+H)+); ES— m/z (rel intensity) 425 (30, (M-H)'), 851 (10, (2MH )').

Aminocyclobutyl)phenyl]—3- 1H-NMR (DMSO-de): 6 [ppm] phenylimidazo[1,2- 1.56-1.72 (m, 1H), 1.92-2.04 b]pyridazine-6,8- (m, 1H), .18 (m, 2H), dicarboxamide (Approach 2) 2.33-2.42 (m, 2H partially obscured by solvent signal), 7.44 (d, J=8.5 Hz, 2H), 7.48- 7.57 (m, 3H), 7.59-7.67 (m, 5H), 7.96 (br s, 1H), 8.20 (d, J=2.6 Hz, 2H), 8.47 (br s, 1H), 9.17 (br s, 1H).

Example Structure/ Name Characterization a UPLC-MS (Method 3): RT = 1.05 min; m/z (rel intensity) 339 (70 (M+H-17)+), 356 (100, (M+H)+); ES— m/z (rel intensity) 337 (30, (M-H-17)'), 851 (10, ((1- (2M-H)').

Aminocyclobutyl)phenyl]—3- 1H-NMR (DMSO-d6): 6 [ppm] imidazo[1,2-b]pyridazin- 1.55-1.66 (m, 1H), 1.90-1.99 6-amine (m, 1H), 2.03-2.11 (m, 2H), 2.30-2.48 (m, 2H), 6.27 (s, 2H), 6.64 (d, J=9.6 Hz, 1H), 7.30 (d, J=8.6 Hz, 2H), 7.38-7.48 (m 7H), 7.75 (d, J=9.6 Hz, 1H), 8.27 (br s, 0.5 H). 36 a UPLC-MS (Method 3): RT = 1.39 min; m/z (rel intensity) 370 (100 (M+H-17)+), 387 (80, (M+H)+). 1H-NMR (DMSO-de): 6 [ppm] 1{4[6()Methylsulfanyl)—3- 1.53-1.66 (m, 1H), .09 phenylimidazo[1,2-b]pyridazin- (m, 5H), 2.28-2.38 (m, 2H), 2-y|]pheny|}cyc|obutanamine 2.42 (s, 3H), 7.18 (d, J=9.4 Hz, 1H), 7.37 (d, J=8.5 Hz, 2H), 7.42-7.59 (m, 7H), 7.98 (d, J=9.4 Hz, 1H).

Example Structure/ Name Characterization 37 UPLC-MS (Method 3): RT = 1.08 min; m/z (rel intensity) 381 "jg—Q I (80 (M+H-17)+), 398 (100, O (M+H)+); ES— m/z (rel intensity) 396 (100, (M-H)'). 4-(1- 1H-NMR (DMSO-de): 6 [ppm] Aminocyclobutyl)phenyl]—3- .67 (m, 1H), 1.88-2.10 phenylimidazo[1,2-b]pyridazin- (m, 3H), 2.05 (s, 3H), 2.28-2.39 6-y|}acetamide (m, 2H), 7.34 (d, J=8.5 Hz, 2H), 7.42-7.54 (m, 7H), 7.92 (br d, J=9.8 Hz, 1H), 8.12 (d, J=9.8 Hz, 1H), 10.69 (br s, 1H). 38 O UPLC-MS (Method 3): RT = O NH2 1.13 min; m/z (rel intensity) 402 I (100 (M+H-17)+), 419 (60, N O (M+H)+), 837 (10, (2M+H)+). o 1H-NMR (DMSO-de): 6 [ppm] N-{2-[4-(1{4-[6- 1.65-1.80 (m, 1H), 1.98-2.13 (MethylsulfonyI) (m, 1H), 2.28-2.39 (m, 2H), phenylimidazo[1,2-b]pyridazin- 3.35 (s, 3H), 7.16 (br s, 2H), 2-y|]pheny|}cyc|obutanamine 7.47 (d, J=8.7 Hz, 2H), 7.51- 7.62 (m, 5H), 7.68 (d, J=8.5 Hz, 2H), 7.77 (d, J=9.4 Hz, 1H), 8.50 (d, J=9.4 Hz, 1H).

Example Structure/ Name Characterization 39 grf UPLC-MS (Method 3): RT = 1.22 min; m/z (rel ity) 382 (100 (M+H-17)+), 399 (50, (M+H)+). 1H-NMR (DMSO-d6): 6 [ppm] Methyl 2--[-4((1- 1.60-1.75 (m, 1H), 1.93-2.08 aminocyclobutyl)phenyI] (m, 1H), 2.15-2.26 (m, 2H), phenylimidazo[1,2- peak obscured by solvent b]pyridazinecarboxylate signal, 3.86 (s, 3H), 7.42 (d, J=8.5 Hz, 2H), 7.50-7.56 (m 5H), 7.62 (d, J=8.5 Hz, 2H), 7.75 (d, J=9.4 Hz, 1H), 8.31 (d, J=9.4 Hz, 1H). 40 .NHZ UPLC-MS (Method 3): RT = O 0.70 min; m/z (rel intensity) 435 (100 (M+H-17)+), 452 (70, (M+H)+); ES— m/z (rel intensity) 450 (100, (M-H)').

N-{2-[4-(1- 1H-NMR ): 6 [ppm] Aminocyclobutyl)phenyl]—3- 1.82-1.90 (m, 1H), 2.11-2.19 phenylimidazo[1,2-b]pyridazin- (m, 1H), 2.64-2.70 (m, 2H), 2,2,2-trifluoroacetamide 6.80 (d, J=9.8 Hz, 1H), 7.42 (d, J=8.3 Hz, 2H), 7.43-7.48 (m 3H), 7.52 (dm, J=7.5 Hz, 2H), 7.58 (d, J=8.3 Hz, 1H), 7.72 (d, J=9.8 Hz, 1H).

Example Structure/ Name Characterization 41 gs’ UPLC-MS (Method 3): RT = 1.33 min; m/z (rel intensity) 402 (100 (M+H-17)+), 419 (80, (M+H)+). 11 NMR (DMSO-d6): 6 [ppm] 1--[4-(6-Bromo 1.62-1.69 (m, 1H), 1.95-2.02 phenylimidazo[1,2-b]pyridazin- (m, 1H), 2.06-2.11 (m, 2H), 2-y|)pheny|]cyc|obutanamine .41 (m, 2H), 7.42 (d, J=8.7 Hz, 1H), 7.49 (d, J=9.4 Hz, 1H), .60 (m, 7H), 8.19 (d, J=9.4 Hz, 1H). 42 :ZCN/N{NH UPLC-MS (Method 3): RT = 1.74 min; m/z (rel intensity) 512 (100 (M+H-17)+), 529 (90, (M+H)+). 11 NMR (DMSO-d6): 6 [ppm] 1.62-1.69 (m, 1H), 1.95-2.02 1--{-4 [6, 8- Bis(4--f-|uoropheny|) (m, 1H), 2.06-2.11 (m, 2H), ylimidazo[1,2- 2.37-2.42 (m, 2H), 7.40 (t, b]pyridazin J=8.7 Hz, 2H), 7.45 (d, J=8.3 y|]pheny|}cyclobutanamine Hz, 2H), 7.49-7.55 (m, 3H), 7.59 (t, J=7.53 Hz, 2H), 7.64 (d, J=8.3 Hz, 2H), 7.69 (2, J=7.2 Hz, 2H), 8.12 (s, 1H), 8.18 (dd, J=9.0, 5.7 Hz, 2H), 8.69 (dd, J=9.0, 5.7 Hz, 2H).

WO 36776 2012/056300 Example Structure/ Name Characterization 43 .NH UPLC-MS (Method 3): RT = 2 1.28 min; m/z (rel intensity) 366 / N’ (100 (M+H-17)+), 383 (90, ‘N O (M+H)+), 765 (5, (2M+H)+).

O 1H-NMR (DMSO-ds): 6 [ppm] 1-{2-[4- ( 1- 1.62-1.70 (m, 1H), 1.96-2.04 Aminocyclobutyl)phenyl]—3- (m, 1H), 2.07-2.12 (m, 2H), phenylimidazo[1,2-b]pyridazin- 2.37-2.43 (m, 2H), 2.56 (s, 3H), 6-y|}ethanone 7.46 (d, J=8.7 Hz, 2H), 7.52- 7.55 (m, 1H), 7.57-7.60 (m, 2H), 7.65-7.69 (m, 4H), 7.74 (d, J=9.4 Hz, 1H), 7.82 (d, J=9.4 Hz, 1H). 44 UPLC-MS (Method 3): RT = 1.53 min; m/z (rel intensity) 418 (100 7)+), 435 (80, (M+H)+). 1-{4-[8—(4-FIuorophenyl) phenylimidazo[1,2-b]pyridazin- 2-yl]phenyl}cyclobutanamine Example Structure/ Name Characterization 45 UPLC-MS (Method 3): RT = 0.69 min; m/z (rel ity) 417 (100 (M+H-17)+), 434 (80, (M+H)+); ES— m/z (rel ity) 432 (100, (M-H)').

N-{2—[4-(1 - 1H-NMR (DMSO-ds): 6 [ppm] yclobuty|)pheny|] 1.64-1.81 (m, 1H), 1.99-2.12 imidazo[1,2—b]pyridazin- (m, 1H), 2.29-2.41 (m, 2H), 6-y|}methanesulfonamide peak obscured by solvent signal, 6.60 (d, J=9.6 Hz, 1H), 7.33-7.44 (m, 5H), 7.53-7.61 (m, 4H), 7.65-7.69 (m, 4H), 7.67 (d, J=9.6 Hz, 1H). 46 UPLC-MS (Method 3): RT = 1.53 min; m/z (rel intensity) 398 (100 (M+H-17)+). 1H-NMR (DMSO-ds): 6 [ppm] 1.23-1.30 (m, 2H), 1.34-1.41 1-[4-(6-ChIorocyclopropyl' (m, 2H), 1.59-1.70 (m, 1H), 3-phenylimidazo[1,2- .03 (m, 1H), 2.09-2.20 b]pyridazin-2— (m, 2H), 2.33-2.39 (m, 1.6H, y|)pheny|]cyc|obutanamine partially obscured by solvent signal), 2.56-2.64 (m, 1.9H, partially obscured by solvent signal), 7.01 (s, 1H), 7.39 (d, J=8.5 Hz, 2H), 7.44-7.53 (m, 5H), 7.56 (d, J=8.3 Hz, 2H).

Example Structure/ Name Characterization 47 UPLC-MS d 3): RT = 1.44 min; m/z (rel intensity) 366 (80 (M+H-17)+), 383 (100 (M+H-17)+). 1H-NMR (DMSO-ds): 6 [ppm] 1-[4-(3-PhenyI 0.98 (t, J=7.4 Hz, 3H), 1.52- propylimidazo[1 ,2—b]pyridazin- 1.66 (m, 1H), 1.84 (apparent 2-yl)phenyl]cyclobutanamine seXt, J=7.6 Hz, 2H), .09 (m, 5H), 2.28-2.38 (m, 2H), 2.99 (q, J=7.5 Hz, 2H), 7.08 (d, J=4.7 Hz, 1H), 7.37 (d, J=8.5 Hz, 2H), 7.43-7.57 (m, 8H). 48 .NH UPLC-MS (Method 3): RT = 1.13 min; m/z (rel ity) 339 (70 (M+H-17)+), 356 (100 _N O (M+H-17)+); ES- m/z (rel intensity) 354 (20, (M-H)'). 2-[4-(1- 1H-NMR (DMSO-ds): 6 [ppm] Aminocyclobutyl)phenyl]—3- 1.54-1.65 (m, 1H), 1.88-2.07 phenylimidazo[1,2—b]pyridazin- (m, 3H), 2.28-2.38 (m, 2H), 8-amine 6.13 (d, J=5.5 Hz, 1H), 6.92 (br s, 2H), 7.34 (d, J=8.5 Hz, 2H), 7.39-7.49 (m, 5H), 7.52 (d, J=8.3 Hz, 2H), 7.89 (d, J=5.5 Hz, 1H).

Example Structure/ Name Characterization 49 UPLC-MS (Method 3): RT = O . >—CHa O NH2 1.23 min; m/z (rel intensity) 381 HN/ 1: I (100 (M+H-17)+), 398 (100 —N’ O (M+H-17)+); ES- m/z (rel ity) 396 (100, (M-H)').

N-{2-[4-(1- 1H-NMR (DMSO-ds): 6 [ppm] Aminocyclobutyl)phenyI] 1.53-1.66 (m, 1H), 1.88-2.15 phenylimidazo[1,2-b]pyridazin- (m, 5H), 2.28-2.38 (m, 2H), 8-y|}acetamide 2.30 (s, 3H), 7.38 (d, J=8.5 Hz, 2H), 7.43-7.52 (m, 5H), 7.59 (d, J=8.3 Hz, 2H), 7.90 (d, J=5.5 Hz, 1H), 8.29 (d, J=5.3 Hz, 1H).

Example 50: 1-[4-(6-Chloro-7,8-dimethylphenylimidazo[1,2-b]pyridazinyl)phenyl]- cyclobutanamine To a mixture of the tert-butyl {1 -[4-(6-ch|oro-7,8-dimethyIphenylimidazo[1 ,2- b]pyridaziny|)phenyl]cyc|obuty|}carbamate that was prepared in a manner us to that described for Intermediate e Int-32 (179 mg, 0.360 mmol, 1.0 eq) in DCM (2.29 mL) and MeOH (1.44 mL) was added a solution of 4 M hydrogen chloride in dioxane (1.78 mL, 7.12 mmol, 20.0 eq) and the mixture was stirred overnight at rt. The mixture was poured onto ice, made alkaline with s sodium hydroxide (2 N) and extracted with DCM. The ed organic phases were washed with brine, dried and concentrated in vacuo. The crude mixture was purified via MPLC (Biotage Isolera; 10 g SNAP WO 36776 cartridge: DCM-> DCM/ethanol 95/5) to give 64 mg (44% yield) of the title compound.

UPLC-MS (Method 2): RT = 1.48 min; m/z = 403 . 1H-NMR (400 MHz, d6-DMSO): 5 [ppm] = 1.59 (m, 1H), 1.93 (m, 1H), 2.02 (m, 2H), 2.11 (brs, 2H), 2.31 (m, 2H), 2.35 (s, 3H), 2.54 (s, 3H), 7.37 (d, 2H), 7.45 - 7.52 (m, 5H), 7.54 (d, 2H).

Example 51: Methyl 2-[4-(1-aminocyclobutyl)phenyI]-7,8-dimethylphenylimidazo[1,2- b]pyridazine—6-carboxylate A mixture of crude tert-butyl (1 -{4- [bromo(phenyl)acetyl]pheny|}cyclobuty|)carbamate [that was prepared in a manner analgous to that described for Intermediate e IntA] (630 mg, ~90% purity, 1.28 mmol, 1.0 eq), methyl 6-amino-4,5-dimethylpyridazine carboxylate [that was prepared in a manner analgous to that described for Intermediate Example Int-34] (257 mg, 1.28 mmol, 1.0 eq), N,N-diisopropylethylamine (220 uL, 1.28 mmol, 1.0 eq) in butyronitrile (2.6 mL) was heated for 17 hours at 125 °C. On cooling the mixture was partitioned between DCM and water, stirred vigorously and ed through a silicone coated filter paper. The filtrate was concentrated in vacuo. The crude mixture was purified via preparative reversed phase HPLC to give 89 mg (16% yield) of the title compound directly as the free amine.

UPLC-MS (Method 2): RT = 1.35 min; m/z = 427 (M+H)+. 1H-NMR (400 MHz, MeOD): 6 [ppm] = 1.75 (m, 1H), 2.06 (m, 1H), 2.24 (m, 2H), 2.44 (s, 3H), 2.55 (m, 2H), 2.71 (s, 3H), 3.93 (s, 3H), 7.38 - 7.47 (m, 5H), 7.48- 7.54 (m, 2H), 7.60 (d, 2H).

Example 52: 2-[4-(1-Aminocyclobutyl)phenyl]-7,8-dimethylphenylimidazo[1,2-b]- pyridazine—6-carboxamide A solution of methyl 2-[4-(1-aminocyc|obutyl)pheny|]-7,8-dimethy| phenylimidazo[1,2-b]pyridazinecarboxylate [that was prepared in a manner analgous to that described for Example 51] (80 mg, ~90% purity, 0.170 mmol, 1.0 eq) in 2.41 ml 7N a in MeOH (~100 eq of NH3) was heated for 2 hours at 130 °C by the use of a single mode ave oven (Biotage). On cooling the volatile ents were removed in vacuo. The crude mixture was purified via MPLC (Biotage Isolera; 11 g SNAP NH2 cartridge: hexane/EtOAc 1:1 -> EtOAc) to give 54 mg (77% yield) of the title compound.

UPLC-MS (Method 2): RT = 1.22 min; m/z = 412 (M+H)+. 1H-NMR (400 MHz, MeOD): 6 [ppm] = 1.74 (m, 1H), 2.06 (m, 1H), 2.24 (m, 2H), 2.48 (s, 3H), 2.55 (m, 2H), 2.70 (s, 3H), 7.38 - 7.48 (m, 5H), 7.52-7.57 (m, 2H), 7.60 (d, 2H). e 53: 1-[4-(6-Methoxy-7,8-dimethylphenylimidazo[1,2-b]pyridazinyl)phenyl]- utanamine To a solution of methyl tert-butyl {1 -[4-(6-methoxy-7,8-dimethyI phenylimidazo[1,2-b]pyridaziny|)pheny|]cyc|obuty|}carbamate [that was prepared in a manner analgous to that described for Intermediate Example Int- 34] (80 mg, ~80% purity, 0.160 mmol, 1.0 eq) in DCM (1.03 mL) and MeOH (0.65 mL) was added a solution of 4 M hydrogen chloride in dioxane (0.80 mL, 3.21 mmol, 20.0 eq) and the mixture was stirred for overnight at rt. The e was poured onto ice, made alkaline with aqueous sodium hydroxide (2 N) and extracted with DCM. The combined organic phases were washed with brine, dried and concentrated in vacuo. The crude mixture was purified via preparative HPLC to give 44 mg (62% yield) of the title compound.

UPLC-MS (Method 2): RT = 1.48 min; m/z = 399 (M+H)+. 1H-NMR (400 MHz, d6-DMSO): 6 [ppm] = 1.61 (m, 1H), 1.94 (m, 1H), 2.05 (m, 2H), 2.16 (s, 3H), 2.34 (m, 2H), 2.52 (s, 3H), 3.81 (s, 3H), 7.32 - 7.42 (m, 3H), 7.45 (m, 2H), 7.51 (m, 2H), 7.55 (m, 2H), NH2 not assigned.

Example 54: 1-{4-[7,8-Dimethyl(methylsulfanyl)—3-phenylimidazo[1,2-b]pyridazinyl]- }cyc|obutanamine To a mixture of the tert-butyl (1 -{4-[7,8-dimethyl(methylsuIfanyl) phenylimidazo[1,2-b]pyridazinyl]pheny|}cyc|obuty|)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int- (95 mg, 0.190 mmol, 1.0 eq) in DCM (1.19 mL) and MeOH (0.75 mL) was added a on of 4 M hydrogen chloride in dioxane (0.92 mL, 3.69 mmol, 20.0 eq) and the mixture was stirred overnight at rt. The mixture was poured onto ice, made alkaline, treated with DCM and filtered through a phase separator. The volatile components of the organic phase were removed in vacuo to give 75 mg (94% yield) of the title compound.

UPLC-MS (Method 2): RT = 1.55 min; m/z = 415 . 1H-NMR (400 MHz, d6-DMSO): 0 [ppm] = 1.60 (m, 1H), 1.87-2.09 (m, 3H), 2.12 (br s, 2H), 2.22 (s, 3H), 2.33 (m, 2H), 2.38 (s, 3H), 2.55 (s, 3H), 7.33 - 7.50 (m, 5H), 7.51-7.60 (m, 4H).

Example 55: 1-[4-(6-Ethoxy-7,8-dimethylphenylimidazo[1,2-b]pyridazinyl)phenyl]- cyclobutanamine To a mixture of the tert-butyl {1-[4-(6-ethoxy-7,8—dimethyIphenylimidazo[1,2- b]pyridazinyl)pheny|]cyc|obuty|}carbamate that was ed in a manner analgous to that described for Intermediate Example Int-36 (210 mg, 0.410 mmol, 1.0 eq) in DCM (2.64 mL) and MeOH (1.66 mL) was added a solution of 4 M en chloride in dioxane (2.05 mL, 8.19 mmol, 20.0 eq) and the mixture was stirred overnight at rt. The e was poured onto ice, made alkaline, d with DCM and filtered through a phase separator. The volatile components of the organic phase were removed in vacuo to give 145 mg (82% yield) of the title compound.

UPLC-MS (Method 2): RT = 1.56 min; m/z = 414 (M+H)+. 1H-NMR (400 MHz, d6-DMSO): 6 [ppm] = 1.30 (t, 3H), 1.59 (m, 1H), 1.87-2.10 (m, 5H), 2.15 (s, 3H), 2.33 (m, 2H), 2.51 (s, 3H), 4.17 (q, 2H), 7.34 (m, 2H), 7.37-7.50 (m, 4H), 7.50-7.56 (m, 3H).

Example 56: Methyl 2-[4-(1-aminocyclobutyl)phenyl]phenyl(1H-pyrazolyl)- imidazo[1 ,2-b]pyridazinecarboxylate A solution of 1-{4-[6-chlorophenyl(1H-pyrazolyl)imidazo[1,2-b]pyridazin- heny|}cyc|obutanamine that was prepared in a manner ana|gous to that bed for Example 19 (0.59 g, 1.34 mmol) in MeOH (2.2 mL) and THF (0.2 mL) in an autoclave was added 1,1’- bis(diphenylphosphino)ferrocenepalladium(ll) dichloride (0.22 g, 0.27 mmol, 0.20 equiv) and triethylamine (0.20 mL, 1.47 mmol, 1.1 equiv.). The ave was flushed with CO (approximately 5 bar) three times, then was pressurized with CO (5.2 bar), stirred at room temperature 30 min., and briefly placed under reduced atmosphere (0.06 bar). The autoclave was then pressurized with CO (5.9 bar at 20 oC), heated to 110 °C, and stirred at this temperature for 22 h.

The resulting solution was concentrated under reduced pressure. The resulting material was purified using MPLC ge a; SNAP 25g cartridge: 100% DCM 2.0 min., gradient to 95% DCM /5% MeOH 1.0 min., 95% DCM /5% MeOH 2.5 min., gradient to 90% DCM /10% MeOH 1.5 min., 90% DCM /10% MeOH 4.5 min.) to give an impure material (0.45 g). A portion of the material was further purified using preparative HPLC (Agilent Prep 1200 equipped with 2 x Prep Pump, DLA, MWD, ELSD and Prep FC using an e C18 5pm 100x30 mm column; gradient from 70% water with 0.2% NH3 / 30% CH3CN to 40% water with 0.2% NH3 / 60% CH3CN over 17.5 min, gradient from 40% water with 0.2% NH3 / 60% CH3CN to 100% CH3CN over 2.5 min) to give methyl 2-[4-(1- aminocyclobutyl)phenyl]phenyl(1 H-pyrazolyl)imidazo[1 ,2-b]pyridazine carboxylate (0.013 g, 17% based on purification of 11%): UPLC-MS (Method 3): RT = 1.28 min; m/z (rel intensity) 448 (100 (M+H-17)+), 465 (80, (M+H)+); ES— m/z (rel intensity) 463 (40, (M-H)'). 1H-NMR (d6-DMSO): 5 1.56-1.67 (m, 1H), 1.91-2.00 (m, 1H), 2.02-2.11 (m, 2H), 2.32-2.39 (m, 2H), 3.88 (s, 3H), 7.42 (d, J=8.6 Hz, 2H), .58 (m, 5H), 7.65 (d, J=8.3 Hz, 2H), 7.77 (d, J=2.3 Hz, 1H), 7.98 (br s, 1H), 8.28 (s, 1H).

The following examples were prepared in a manner analogous to Example 56 by reacting the corresponding halide with MeOH and CO in the presence of 1,1’- bis(diphenylphosphino)ferrocenepalladium(ll) dichloride 2012/056300 Structure/ Name Characterization .6? UPLC-MS (Method 3): RT = 1.29 min; m/z (rel intensity) 426 (100 (M+H-17)+), 443 (100, (M+H)+). 1H-NMR (DMSO-de): 6 [ppm] Methyl ((1- 1.48 (t, J=7.1 Hz, 3H), 1.56- aminocyclobutyl)phenyI] 1.65 (m, 1H), 1.89-2.14 (m ethoxyphenylimidazo[1,2- 5H), 2.29-2.36 (m, 2H), 3.85 (s, b]pyridazinecarboxylate 3H), 4.47 (q, J=7.1 Hz, 2H), 7.14 (s, 1H), 7.37 (d, J=8.6 Hz, 2H), 7.47-7.54 (m, 7H).

UPLC-MS (Method 3): RT = 1.25 min; m/z (rel intensity) 448 (100 (M+H-17)+), 465 (80, (M+H)+), 929 (20, (2M+H)+). 1H-NMR (DMSO-de): 6 [ppm] Methyl 2-[4-(1- 1.57-1.68 (m, 1H), 12.90-2.00 aminocyclobutyl)phenyI] (m, 1H), 2.02-2.12 (m, 2H), (1 H-imidazoIyI) .39 (m, 2H), 3.90 (s, 3H), phenylimidazo[1,2- 7.27 (s, 1H), 7.43 (d, J=8.5 Hz, b]pyridazinecarboxylate 2H), 7.52-7.59 (m, 6H), 7.63 (d, J=8.5 Hz, 2H), 8.09 (s, 1H), 8.57 (s, 1H), 9.31 (s, 1H).

Example 59: utyl {1 -[4-(8-acetamidophenylimidazo[1 ,2-b]pyridazinyl)phenyl]- cyclobutyl}carbamate A solution of methyl 2-[4-(1-aminocyclobutyl)pheny|]phenylimidazo[1,2- b]pyridazinecarboxylate that was prepared in a manner analgous to that described for Example 31 (0.040 g, 0.10 mmol) in a solution of ammonia in MeOH (7 N, 0.7 mL, 5.0 mmol, 50 equiv) was irradiated in a microwave apparatus at 130 °C for 90 min. The resulting e was concentrated under reduced pressure. The resulting material was triturated with diisopropyl ether to give tert-butyl {1 -[4-(8-acetamidophenylimidazo[1 ,2-b]pyridazin yl)pheny|]cyc|obutyl}carbamate (0.025 g, 60%): S (Method 3): RT = 1.17 min; m/z (rel intensity) 367 (100, (M+H-17)+), 384 (70, (M+H)+). 1H-NMR de): 6 [ppm] 1.54-1.69 (m, 1H), 1.90-2.01 (m, 1H), 2.03-2.13 (m, 2H), 2.31-2.40 (m, 2H), 7.41 (d, J=8.5 Hz, 2H), 7.48-7.56 (m, 5H), 7.61 (d, J=8.5 Hz, 2H), 7.75 (d, J=4.7 Hz, 1H), 8.41 (br s, 1H), 8.63 (d, J=4.7 Hz, 1H), 9.25 (br s, 1H).

The following es were prepared in a manner analogous to Example 59 by reacting the corresponding ester with ammonia 2012/056300 Structure/ Name Characterization UPLC-MS (Method 3): RT = 1.11 min; m/z (rel intensity) 433 (100 (M+H-17)+), 450 (80, (M+H)+), 921 (10, (2M+Na)+); ES— m/z (rel intensity) 448 (100, (M-H)')- Aminocyclobutyl)phenyl]—3- 1H-NMR (DMSO-de): 6 [ppm] phenyl(1H-pyrazol 1.56-1.68 (m, 1H), 1.89-2.10 yl)imidazo[1,2—b]pyridazine (m, 3H), 2.31-2.41 (m, 3H), carboxamide 7.43 (d, J=8.5 Hz, 2H), 7.47- 7.56 (m, 4H), 7.62-7.68 (m, 4H), 7.75 (d, J=2.0 Hz, 1H), 7.85 (br s, 1H), 7.95 (br s, 1H), 8.25 (s, 1H). 61 UPLC-MS (Method 3): RT = 1.11 min; m/z (rel intensity) 411 (60 (M+H-17)+), 428 (70, (M+H)+); ES— m/z (rel intensity) 446 (10, (M-H)'). 2—[4-(1 - 1H-NMR (DMSO-de): 6 [ppm] Aminocyclobutyl)phenyl]—8— 1.47 (t, J=7.1 Hz, 3H), 1.57- ethoxyphenylimidazo[1,2- 1.65 (m, 1H), 1.89-2.14 (m, b]pyridazinecarboxamide 5H), .37 (m, 2H), 4.45 (q, J=7.1 Hz, 2H), 7.12 (s, 1H), 7.37 (d, J=8.3 Hz, 2H), 7.43- 7.55 (m, 2H), 7.62-7.68 (m, 6H), 7.59 (d, J=8.1 Hz, 2H), 7.82 (br s, 1H).

The following examples were prepared in a manner ous to Example 59 by ng the corresponding ester with methylamine W0 2012/136776 Example Structure/ Name Characterization 62 1H-NMR (CD30D): 6 [ppm] 1.70-1.82 (m, 1H), 1.99-2.14 (m, 1H), 2.19-2.31 (m, 2H), 2.50-2.61 (m, 2H), 7.29 (s, 1H), 7.40 (d, J=8.5 Hz, 2H), 7.52- 2-[4-(1- 7.61 (m, 5H), 7.68 (d, J=8.5 Hz, Aminocyclobuty|)pheny|] 2H), 7.99 (s, 1H), 8.33 (s, 1H), (1H-imidazoIy|)-N-methyI 9.38 (s, 1H). phenylimidazo[1,2— b]pyridazinecarboxamide 63 UPLC-MS (Method 3): RT = H30 .

‘NH O NH2 1.25 min; m/z (rel intensity) 381 0:8) (100 (M+H-17)+), 398 (50, -N’ O (M+H)+). 1H-NMR (DMSO-de): 6 [ppm] 1.60-1.70 (m, 1H), .03 Aminocyclobutyl)phenyI]-N- (m, 1H), 2.07-2.14 (m, 2H), phenylimidazo[1,2- 2.35-2.43 (m, 2H), 3.05 (d, b]pyridazine-8—carboxamide J=4.8 Hz, 3H), 7.44 (d, J=8.5 Hz, 2H), 7.51-7.57 (m, 5H), 7.68 (d, J=8.5 Hz, 2H), 7.79 (d, J=4.5 Hz, 1H), 8.66 (d, J=4.5 Hz, 1H), 9.75 (q, J=4.5 Hz, 1H).

Example Structure/ Name Characterization 64 <8 9 UPLC-MS (Method 3): RT = NH2 1.27 min; m/z (rel intensity) 451 O /N O / ’ (70 (M+H-17)+), 468 (100, HagH _N O ), 935 (70, +); ES— m/z (rel intensity) 466 (100, 2-[4-(1- (M-H)'), 933 (10, (2M-H)'), Aminocyclobutyl)phenyl]—8- 1H-NMR (DMSO-de): 6 [ppm] (cyclopropylmethoxy)-N- 0.41-0.46 (m, 2H), 0.62-0.68 methylphenylimidazo[1,2- (m, 2H), 1.33-1.41 (m, 1H), b]pyridazinecarboxamide 1.55-1.65 (m, 1H), 1.90-2.10 (m, 5H), 2.29-2.37 (m, 2H), 2.77 (d, J=4.8 Hz, 3H), 4.24 (d, J=7.3 Hz, 2H), 7.08 (s, 1H), 7.37 (d, J=8.3 Hz, 2H), 7.45- 7.53 (m, 5H), 7.58 (d, J=6.8 Hz, 2H), 8.08 (q, J=4.6 Hz, 1H). 65 UPLC-MS d 3): RT = 1.18 min; m/z (rel intensity) 447 (100 (M+H-17)+), 464 (90, (M+H)+), 927 (5, +); ES- m/z (rel intensity) 462 (40, (M- 2-[4-(1- H)'), 925 (10, (2M-H)'), Aminocyclobutyl)phenyI]-N- 1H-NMR (DMSO-de): 6 [ppm] methylphenyl(1H- 1.56-1.66 (m, 1H), 1.90-1.99 pyrazoIyl)imidazo[1,2- (m, 1H), 2.00-2.09 (m, 2H), b]pyridazinecarboxamide 2.31-2.39 (m, 2H), 2.80 (d, J=4.8 Hz, 3H), 7.42 (d, J=8.3 Hz, 2H), 7.48-7.55 (m, 3H),7.61-7.65 (m, 4H), 7.75 (d, J=2.3 Hz, 1H), 7.95 (br d, J=1 .8 Hz, 1H), 8.15 (br q, J=4.8 Hz, e Structure/ Name Characterization 1 H), 8.24 (s, 1 H).

The following examples were prepared in a manner analogous to Example 59 by reacting the corresponding ester with ethylamine ture/ Name Characterization 66 . UPLC-MS (Method 3): RT = NH2 1.17 min; m/z (rel intensity) 395 / I (100 (M+H-17)+), 412 (50, (CH3 ‘Nfl H O o 1H-NMR de): 5 [ppm] 2-[4-(1- 1.07 (t, J=7.1 Hz, 3H), 1.72- Aminocyclobutyl)phenyI]-N- 1.84 (m, 1H), peak obscured by ethylphenylimidazo[1,2— solvent signal, 2.05-2.16 (m, b]pyridazinecarboxamide 1H), 254-255 (m, 2H), 231. 3.27 (q, J=7.3 HZ, 2H), 7.46- 7.55 (m, 5H),7.61 (dd; J=7.6, 1.5 Hz, 2H), 7.68 (d, J=8.6 Hz, 2H), 7.73 (d, J=9.4 Hz, 1H), 8.30 (d, J=9.4 Hz, 1H), 8.15 (br q, J=4.8 Hz, 1H), 8.24 (s, 1H).

Example 67: 2-[4-(1-Aminocyclobutyl)phenyl]phenyl(1H-pyrazolyl)imidazo[1,2-b]- pyridazine—6-carboxylic acid To a solution of methyl 2-[4-(1-aminocyclobutyl)phenyl]phenyl(1H-pyrazol- 3-yl)imidazo[1,2-b]pyridazinecarboxylate that was prepared in a manner analgous to that described for Example 56 (0.19 g, 0.41 mmol) in MeOH (5 mL) was added an s NaOH solution (10% 0.65 mL, 1.64 mmol, 4.0 equiv).

The resulting mixture was stirred at room temperature for 48h. Water 10 mL) was added to the resulting mixture and the pH was adjusted to pH 4 using an aqueous 2N HCI solution. The resulting precipate was collected by filtration, and recrystallized from dimethyl sulfoxide to give 2-[4-(1- aminocyclobutyl)phenyl]phenyl(1 H-pyrazolyl)imidazo[1 ,2-b]pyridazine carboxylic acid (0.012 g, 6%).

UPLC-MS (Method 3): RT = 0.70 min; m/z (rel intensity) 434 (40 (M+H-17)+), 451 (100, (M+H)+); ES- m/z (rel intensity) 449 (70, (M-H)'), 899 (50, (2M-H)'), 1H-NMR (DMSO-de): 6 [ppm] 1.70-1.83 (m, 1H), 2.04-2.17 (m, 1H), 2.03-2.13 (m, 2H), 2.53-2.64 (m, 3.5H partially obscured by solvent signal), 7.50 (d, J=8.5 Hz, 2H), 7.52-7.58 (m, 5H), 7.75-7.80 (m, 3H), 7.97 (d, J=2.3 Hz, 1H), 8.30 (s, 1H). e 68: 2-[4-(1-Aminocyclobutyl)phenyl]-N-methylphenylimidazo[1,2-b]- pyridazine—6-carboxamide To a solution of 2-[4-(1-aminocyclobuty|)pheny|]pheny|imidazo[1,2- b]pyridazinecarboxylic acid that was prepared in a manner analgous to that bed for Example 8 (0.15 g, 0.39 mmol) and methylamine (2 M in THF, 1.43 mL, 2.93 mmol, 7.5 equiv) in DMF (1 mL) was added PYBOP (0.22 g, 0.43 mmol 1.10 equiv) and N,N-diisopropylethylamine (0.27 mL, 1.56 mmol, 4.0 . The ing mixture was stirred at room temperature for 25 h, then was d with water (10 mL). The resulting aqueous mixture was extracted with EtOAc (4 x 15 mL). The combined organic phases were washed with water (2 x mL), dried (Na2SO4 anh.) and trated under reduced pressure. The resulting material was triturated with MeOH to give 2-[4-(1- yclobutyl)phenyl]—N-methylphenylimidazo[1,2-b]pyridazine carboxamide (0.085 g, 55%): UPLC-MS (Method 3): RT = 1.09 min; m/z (rel intensity) 381 (100 (M+H-17)+), 398 (70, (M+H)+), 795 (10, (2M+H)+); ES- m/z (rel intensity) 396 (40, (M-H)'). 1H-NMR (DMSO-de): 6 [ppm] 1.55-1.66 (m, 1H), 1.89-2.08 (m, 5H), 2.28-2.38 (m, 2H), 2.78 (d, J=4.7 Hz, 3H), 7.38 (d, J=8.3 Hz, 2H), 7.46-7.56 (m, 5H), 7.61 (dd, J=7.7, 1.3 Hz, 2H), 7.68 (d, J=9.4 Hz, 1H), 8.16 (br q, J=4.7 Hz, 1H), 8.26 (s, 1H).

The ing examples were prepared in a manner analogous to Example 68 by the PYBOP-mediated reaction of the appropriate carboxylic acid with the appropriate amine Example ure/ Name Characterization 69 UPLC-MS (Method 3): RT = 1.09 min; m/z (rel intensity) 395 (100 (M+H-17)+), 412 (90, (M+H)+), 823 (10, +); ES— m/z (rel intensity) 426 (100, 2-[4-(1- (M-H)'), 853 (10, (2M-H)').

Aminocyclobutyl)phenyl]-N,N- 1H-NMR (DMSO-de): 5 [ppm] dimethylphenylimidazo[1,2- 1.56-1.65 (m, 1H), 1.89-2.07 b]pyridazinecarboxamide (m, 5H), 2.28-2.36 (m, 2H), 2.97 (s, 3H), 2.99 (s, 3H), 7.36- 7.39 (m, 3H), 7.45-7.54 (m, 5H),7.57 (d; J=8.3 Hz, 2H), 8.24 (d, J=9.4 Hz, 1H).

Example Structure/ Name Characterization 70 UPLC-MS (Method 3): RT = O NH2 0.99 min; m/z (rel intensity) 411 HO/iJ]<90 (100 (M+H-17)+), 427 (80, (M+H)+), 855 (10, (2M+H)+). 0 1H-NMR (DMSO-de): 6 [ppm] 1- 1.58-1.66 (m, 1H), 1.90-2.08 yclobutyl)phenyl]—N-(2- (m, 5H), 2.29-2.37 (m, 2H), hydroxyethyI) 3.33 (q, J=5.8 Hz, 2H), 3.47 (q, phenylimidazo[1,2- J=5.6 Hz, 2H), 4.75 (t, J=5.3 b]pyridazinecarboxamide Hz, 1H), 7.39 (d, J=8.3 Hz, 2H), 7.45-7.54 (m, 3H),7.56 (d; J=8.3 Hz, 2H), 7.61 (dm, J=8.3 Hz, 2H), 7.70 (d, J=9.4 Hz, 1H), 8.06 (t, J=6.1 Hz, 1H), 8.28 (d, J=9.60 Hz, 1H). 71 UPLC-MS (Method 3): RT = 1.02 min; m/z (rel intensity) 477 (60 (M+H-17)+), 494 (100, (M+H)+); ES— m/z (rel intensity) 492 (20, (M-H)'). 2-[4-(1- 1H-NMR (DMSO-de): 6 [ppm] yclobutyl)phenyl]—N-(2- 1.56-1.66 (m, 1H), 1.90-2.14 hydroxyethyI)phenyI(1H- (m, 5H), 2.32-2.39 (m, 2H), pyrazoIyl)imidazo[1,2- 3.36 (q, J=5.8 Hz, 2H), 3.49 (q, b]pyridazinecarboxamide J=5.6 Hz, 2H), 4.76 (t, J=5.3 Hz, 1H), 7.42 (d, J=8.6 Hz, 2H), 7.47-7.55 (m, 3H), .67 (m, 4H),7.76 (d, J=2.3 Hz, 1H), 7.94 (br s, 1H), 8.05 (br t, J=5.6 Hz, 1H), 8.27 (s, 1H).

Example 72: Methyl 3-{2-[4—(1-aminocyclobutyl)phenyl]phenylimidazo[1,2-b]pyridazin- 8-yl}propanoate Step 1: Methyl -[6-bromo(4-{1-[(tert-butoxycarbonyl)amino]cyclo- butyl}phenyl)—3-phenylimidazo[1,2-b]pyridazin-8—yl]acrylate 0 ji OHS N o/1\CH3 H CH3 A on of utyl (1-{4-[3-phenyI-6,8-dibromoimidazo[1,2-b]pyridazin yl]pheny|}cyc|obutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-6 (0.50 g, 0.84 mmol), methyl acrylate (0.11 mL, 1.3 mmol, 1.5 equiv) and triethylamine (0.13 mL, 0.96 mmol, 1.1 equiv) in acetonitrile (6 mL) was placed under an argvon atmosphere. To this was added tri(2-tolyl)phosphine (0.043 g, 0.14 mmol, 0.17 equiv) and palladium(|l) acetate (0.013 g, 0.059 mmol, 0.07 equiv). The resulting mixture was irradiated in a microwave apparatus at 150 °C for 60 min. The resulting mixture was then added to water (15 mL). The resulting mixture was extracted with EtOAc (2x25 mL). The combined organic phases were washed with water (25 mL), dried (Na2804), and concentrated under reduced pressure. The resulting material was purified using MPLC (Biotage Isolera; Snap 10g cartridge, 100% hexane 1.5 min, gradient to 80% hexane / 20% EtOAc 1.0 min, 80% hexane / 20% EtOAc 2.0 min, gradient to 50% hexane / 50% EtOAc 3.0 min, 50% hexane / 50% EtOAc 4.0 min, gradient to 100% EtOAc 4.5 min, 100% EtOAc 7.7 min) to give methyl (2E)[6-bromo(4-{1-[(tert- butoxycarbonyl)amino]cyc|obutyl}phenyI)phenylimidazo[1,2-b]pyridazin-8— y|]acry|ate (0.50 g, 99%) which was used without r purification.

Step 2: Methyl 3-{2-[4-(1-aminocyclobutyl)phenyl]phenylimidazo[1,2-b]- pyridazinyl}propanoate To a mixture of methyl (2E)[6-bromo(4-{1-[(tert- butoxycarbony|)amino]cyc|obuty|}pheny|)phenylimidazo[1,2-b]pyridazin y|]acry|ate that was prepared in a manner ana|gous to that described for Example 72, Step 1 (0.50 g, 0.83 mmol) and 10% palladium on carbon (0.26 g) in a mixture of ethanol (14 mL) and THF (5 mL) was placed under a hydrogen atmosphere at room ature for 1 h. The resulting mixture was treated with additional 10% palladium on carbon (0.26 g) and placed under a hydrogen here for 1 h. Solids were removed by filtration and washed with ethanol (20 mL). The ed organic solutions were treated with 10% palladium on carbon (0.26 g) and placed under a hydrogen atmosphere for 1 h. Solids were removed by filtration and washed with l (20 mL). The combined organic solutions were concentrated under reduced pressure. The resulting material was purified using MPLC (Biotage |so|era; Snap 25g cartridge, 100% hexane 2.0 min, gradient to 80% hexane / 20% EtOAc 1.5 min, gradient to 74% hexane /26% EtOAc 2.5 min, gradient to 70% hexane / 30% EtOAc 2.0 min, nt to 50% hexane / 50% EtOAc 3.0 min, 50% hexane / 50% EtOAc 6.4 min, n to 25% hexane / 75% EtOAc 3.5 min, 25% hexane / 75% EtOAc 5.3 min gradient to 100% EtOAc 5.3 min, 100% EtOAc 21.2 min). The resulting material was further purified using preparative HPLC (Agilent Prep 1200 equipped with 2 x Prep Pump, DLA, MWD, ELSD and Prep FC using an XBrigde C18 5pm 100x30 mm column; gradient from 100% water with 0.1% HCOzH to 70% water with 0.1% HCOzH / 30% MeOH over 1.0 min, gradient to 30% water with 0.1% HCOzH / 70% MeOH over 7.0 min, gradient to 100% MeOH over 0.1 min, 100% MeOH 1.9 min) to give methyl 3-{2-[4-(1-aminocyclobuty|)pheny|] phenylimidazo[1,2-b]pyridaziny|}propanoate (0.003 g, 1%): UPLC-MS d 3): RT = 0.97 min; m/z (rel intensity) 410 (500 (M+H-17)+), 427 (60, (M+H)+). 1H-NMR (CD30D): 6 [ppm] 1.76-1.89 (m, 1H), 2.04-2.18 (m, 1H), 2.30-2.41 (m, 2H), 2.58-2.69 (m, 2H), 2.97 (t, J=7.4 Hz, 2H), 3.40 (t, J=7.5 Hz, 2H), 3.68 (s, 3H), 7.10 (d, J=4.5 Hz, 1H), 7.41-7.47 (m, 5H), 7.48-7.53 (m, 2H), 7.65 (d, J=8.5 Hz, 2H), 8.29 (d, J=4.7 Hz, 1H).

Example 73: 1-{4-[6-Methoxy—3-phenyl-8—(1H-pyrazolyl)imidazo[1,2-b]pyridazinyl]- phenyl}cyc|obutanamine To a solution of 6-ch|oropheny|(1H-pyrazoIyl)imidazo[1,2- b]pyridaziny|]phenyl}cyc|obutanamine that was prepared in a manner analgous to that described for Example 19 (0.14 g, 0.32 mmol) and sodium methoxide (0.051 g, 0.95 mmol, 3.0 equiv) in MeOH (0.8 mL) was irradiated in a microwave apparatus at 120 °C for 90 min. The resulting mixture was added to water 10 mL. The aqueous mixture was extracted with DCM (3 x 15 mL), dried (Na2804 anh.) and concentrated under reduced pressure. The resulting material was ed using MPLC (Biotage Isolera; Snap 10g cartridge, 100% hexane 2.0 min, gradient to 80% hexane / 20% EtOAc 1.0 min, 80% hexane/ % EtOAc 3.0 min, gradient to 50% hexane / 50% EtOAc 2.5 min, 50% hexane /50% EtOAc 3.5 min, gradient to 100% EtOAc 3.0 min, 100% EtOAc 4.8 min) to give an oil which was ated with MeOH to give 6-methoxyphenyI (1 H-pyrazolyl)imidazo[1 ,2-b]pyridazinyl]phenyl}cyc|obutanamine (0.052 g, 36%): UPLC-MS (Method 3): RT = 1.37 min; m/z (rel intensity) 420 (100 (M+H-17)+), 437 (60, (M+H)+); ES— m/z (rel intensity) 435 (80, (M-H)'). 1H-NMR (DMSO-de): 0 [ppm] 1.55-1.66 (m, 1H), 1.87-2.13 (m, 5H), 2.29-2.39 (m, 2H), 3.82 (s, 3H), 7.32 (s, 1H), 7.39 (d, J=8.5 Hz, 2H), 7.42-7.53 (m, 3H), 7.56-7.62 (m, 4H), 7.69 (d, J=2.1 Hz, 1H), 7.91 (br s, 1H).

The following examples were prepared in a manner analogous to Example 73 by the reaction of the sodium methoxide with the appropriate halide Characterization UPLC-MS d 3): RT = 1.38 min; m/z (rel ity) 434 (100 (M+H-17)+), 451 (80, (M+H)+), 901 (20, (2M+H)+). 1H-NMR (DMSO-de): 6 [ppm] 1-{4-[6—Methoxy-8—(1-methyl- 1.51-1.65 (m, 1H), 1.85-2.15 1H-pyrazolyl) (m, 5H), 2.27-2.37 (m, 2H), phenylimidazo[1,2—b]pyridazin- 3.84 (s, 3H), 4.02 (s, 3H), 6.92 2-yl]phenyl}cyclobutanamine (d, J=1.9 Hz, 1H), 7.06 (s, 1H), 7.35 (d, J=8.5 Hz, 2H), 7.43- 7.53 (m, 5H),7.57-7.62 (m, 3H). 75 1H-NMR (DMSO-de): 5 [ppm] 1.60-1.65 (m, 1H), .02 (m, 1H), 2.05-2.14 (m, 4H), .41 (m, 2H), 3.90 (s, 3H), 7.43 (d, J=8.5 Hz, 2H), 7.46 (s, 1-{4-[6—Methoxyphenyl'8' 1H), 7.48-7.59 (m, 5H),7.65 (pyridinyl)imidazo[1,2- (dM, J=7.3 Hz, 2H), 8.41 (d, b]pyridazin J=6.3 Hz, 2H), 8.83 (d, J=6.3 yl]phenyl}cyclobutanamine HZ, 2H).

The following examples were prepared in a manner ous to Example 73 by the reaction of the sodium ethoxide with the appropriate halide WO 36776 mStructure/ Name Characterization cf UPLC-MS d 3): RT = 1.46 min; m/z (rel intensity) 412 (100 (M+H-17)+), 429 (90, (M+H)+), 857 (50, (2M+H)+). 1H-NMR (DMSO-de): 6 [ppm] 1--[4-((6 8- Diethoxy 1.27 (t, J=7.1 Hz, 3H), 1.43 (t, phenylimidazo[1,2-b]pyridazin- J=7.1 HZ, 3H), 1.56-1.64 (m 2-yl)phenyl]cyclobutanamine 1H), 1.89-2.09 (m, 5H), 2.28- 2.36 (m, 2H), 4.15 (q, J=7.1 Hz, 2H), 4.32 (q, J=7.1 Hz, 2H), 6.36 (s, 1H), 7.34 (d, J=8.6 Hz, 2H), 7.38-7.48 (m, 5H),7.52 (dm, J=8.1 Hz, 2H).

Example 77: 1-[4-(8-Butoxyethoxyphenylimidazo[1 ,2-b]pyridazinyl)phenyl]- cyclobutanamine ":H30 09NH2 I A mixture of ethyl {1-[4-(6,8—diethoxyphenylimidazo[1,2-b]pyridazin yl)phenyl]cyc|obutyl}carbamate (0.12 g, 0.24 mmol) and potassium hydroxide (powder, 0.077 g, 1.17 mmol, 5.0 equiv) in n-butanol (2.5 mL) was heated at the reflux temperature for 24 h. The resulting e was cooled to room temperature and separated between a 4:1 DCM / isopropanol solution (50 mL) and water 50 mL). The organic phase was washed with a ted aqueous NaCI solution (25 mL), dried (Na2804 anh.) and concentrated under reduced pressure. The resulting al was purified using MPLC (Biotage Isolera; SNAP 10g cartridge: 100% DCM 4.0 min., gradient to 95% DCM /5% MeOH 1 WO 36776 min., 95% DCM /5% MeOH 3.5 min., gradient to 90% DCM /10% MeOH 1 min., 90% DCM /10% MeOH 3.5 min., gradient to 80% DCM /20% MeOH 6 min., 80% DCM /20% MeOH 4.7 min.) to give 1-[4-(8-butoxyethoxy phenylimidazo[1,2-b]pyridaziny|)pheny|]cyc|obutanamine (0.013 g, 9%): 1H-NMR (DMSO-d6): 6 [ppm] 0.97 (t, J: 7. 5 Hz, 3H), 1.30 (t, J=7.0 Hz, 3H), 1.49 (sext, J=7.5 Hz, 2H), .67 (m, 1H), 1.83 apparent (pent, J=7.0 Hz, 2H), .24 (m, 5H), 2.31-2.39 (m, 2H), 4.17 (q, J=7.3 Hz, 2H), 4.30 (t, J=6.6 Hz, 2H), 6.40 (s, 1H), 7.37 (d, J=8.5 Hz, 2H), 7.40-7.50 (m, 5H), 7.53-7.56 (m, 2H).

Example 78: 1-[4-(6-Ethoxyphenylimidazo[1,2-b]pyridazinyl)phenyl]cyclobutan- amine A mixture of tert-butyl {1- [4-(6(-ch|oro phenylimidazo[1, 2-b-]pyridazin- yl)pheny|]cyc|obuty|}carbamate that was prepared in a manner analgous to that described for ediate Example Int-6.2 (0.050 g, 0.11 mmol) and potassium hydroxide (powder, 0.050 g, 0.89 mmol, 8.5 equiv) in ethanol (0.8 mL) was irradiated in a microwave apparatus at 120 °C for 120 min. The resulting mixture was added to ice water (10 mL). The aqueous mixture was extracted with a 4:1 DCM / isopropanol solution (4 x 10 mL). The combined organic phases were dried (NazSO4 anh.) and concentrated under reduced re.

The ing material was purified using MPLC (Biotage |so|era; SNAP 10g cartridge: 100% DCM 4.0 min., gradient to 95% DCM /5% MeOH 1 min., 95% DCM /5% MeOH 3.5 min., gradient to 90% DCM /10% MeOH 1 min., 90% DCM /10% MeOH 3.5 min., gradient to 80% DCM /20% MeOH 6 min., 80% DCM /20% MeOH 4.7 min.) to give 1-[4-(6—ethoxyphenylimidazo[1,2-b]pyridazin y|)pheny|]cyc|obutanamine (0.017 g, 42%): UPLC-MS (Method 3): RT = 1.39 min; m/z (re| intensity) 368 (100 (M+H-17)+), 385 (80, (M+H)+), 769 (10, (2M+H)+). 1H-NMR (DMSO-ds): 6 [ppm] 1.28 (t, J=7.0 Hz, 3H), 1.53-1.65 (m, 1H), 1.87- 2.08 (m, 5H), 2.27-2.33 (m, 2H), 4.18 (q, J=7.0 Hz, 2H), 6.88 (d, J=9.6 Hz, 1H), 1H), 7.35 (d, J=8.5 Hz, 2H), 7.41-7.56 (m, 7H), 8.03 (d, J=9.6 Hz, 1H).

Example 79: 1-Aminocyclobutyl)phenyl]phenylimidazo[1,2-b]pyridazinol A mixture of tert-buty|((1--{-4[3-phenyl--methoxyimidazo[1, 2- b]pyridazin- yl]pheny|}cyc|obutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-5 (0.25 g, 0.53 mmol) in N- methylpyrrolidone (5 mL) was warmed to 100 °C, then sodium sulfide (0.21 g, 2.66 mmol, 5.0 equiv) was added and the mixture was heated to 160 °C for 10 minutes. The resulting mixture was added to ice water (15 mL). The aqueous mixture was made acidic with an aqueous 2 N HCI solution, then was buffered with a saturated s sodium onate solution. The resulting precipitate was removed by filtration, washed with water, and dried at 50 °C under vacuum to give 2-[4-(1-Aminocyclobutyl)phenyl]—3-phenylimidazo[1,2-b]pyridazino| (0.10 g, 53%): UPLC-MS (Method 3): RT = 0.61 min; m/z (rel ity) 340 (100 (M+H-17)+), 357 (90, (M+H)+), 713 (20, (2M+H)+); ES- m/z (rel ity) 355 (100, (M-H)'), 711 (100, (2M-H)-). 1H-NMR (DMSO-d6): 6 [ppm] 1 .5-51 .66 (m, 1H), 1.86-1.99 (m, 1H), 2.20-2.11 (m, 2H), 2.30-2.38 (m, 2H), 6.70 (d, J=9.6 Hz, 1H), 7.32 (d, J=8.3 Hz, 2H), 7.38- 7.49 (m, 7H), 7.88 (d, J=9.6 Hz, 1H). e 80: Methyl ({2-[4-(1-aminocyclobutyl)phenyl]phenylimidazo[1,2-b]pyridazin- 6-yl}oxy)acetate To a solution of ((1-a-minocyclobutyl) pheny|]---3phenylimidazo[1, 2- dazino| that was ed'In a manner analgous to that described for Example 79 (0.093 g, 0.26 mmol) in DMF (2.5 mL) was added cesium carbonate (0.26 g, 0.79 mmol, 3.0 equiv) and bromoacetic acid methyl ester (0.03 mL, 0.31 mmol, 1.20 equiv). The resulting mixture was stirred at room temperature for 1 h, then was warmed to 60 °C for 3 h. The resulting mixture was diluted with water (10 mL). The aqueous mixture was extracted with EtOAC (3 x 10 mL). The combined organic phases were dried (Na2804 anh.) and concentrated under reduced pressure. The resulting material was further purified using preparative HPLC (Agilent Prep 1200 equipped with 2 x Prep Pump, DLA, MWD, ELSD and Prep FC using an XBrigde C18 5pm 100x30 mm column; gradient from 100% water with 0.1% HCOzH to 70% water with 0.1% HCOzH / 30% MeOH over 1.0 min, gradient to 30% water with 0.1% HCOzH/ 70% MeOH over 7.0 min, gradient to 100% MeOH over 0.1 min, 100% MeOH 1.9 min) to give methyl -(1-aminocyclobutyl)phenyl]—3-phenylimidazo[1,2- b]pyridaziny|}oxy)acetate (0.056 g, 49%): UPLC-MS (Method 3): RT = 1.21 min; m/z (rel intensity) 412 (100 (M+H-17)+), 429 (60, (M+H)+), 857 (10, (2M+H)+). 1H-NMR (DMSO-d6): 6 [ppm] 1 5.4-1.68 (m, 1H), 1.86-2.11 (m, 3H), 2.30-2.39 (m, 2H), 3.56 (s, 3H), 4.81 (s, 2H), 7.03 (d, J=9.6 Hz, 1H), 7.37 (d, J=8.5 Hz, 2H), 7.41-7.47 (m, 5H), 7.52 (d, J=8.5 Hz, 2H), 8.12 (d, J=9.6 Hz, 1H).

Biological igations The following assays can be used to illustrate the commercial utility of the compounds according to the present invention. es were tested in selected biological assays one or more times. When tested more than once, data are reported as either average values or as median values, wherein -the average value, also referred to as the arithmetic mean value, represents the sum of the values obtained divided by the number of times tested, and -the median value represents the middle number of the group of values when ranked in ascending or descending order. If the number of values in the data set is odd, the median is the middle value. If the number of values in the data set is even, the median is the arithmetic mean of the two middle values.

Examples were synthesized one or more times. When synthesized more than once, data from biological assays represent e values or median values calculated utilizing data sets obtained from testing of one or more synthetic batch.

Biological Assay 1.0: Akt1 kinase assay Akt1 inhibitory activity of nds of the t invention was quantified employing the Akt1 TR-FRET assay as described in the following paragraphs.

His-tagged human recombinant kinase full-length Akt1 expressed in insect cells was sed form Invitrogen (part number PV 3599). As substrate for the kinase reaction the biotinylated peptide biotin-Ahx-KKLNRTLSFAEPG (C- terminus in amide form) was used which can be purchased e.g. from the company Biosynthan GmbH (Berlin-Buch, Germany).

For the assay 50 hi of a 100fo|d concentrated solution of the test compound in DMSO was ed into a black low volume 384we|| microtiter plate (Greiner Bio-One, Frickenhausen, y), 2 ul of a solution of Akt1 in assay buffer [50 mM TRIS/HCI pH 7.5, 5 mM MgCIz, 1 mM dithiothreitol, 0.02% (v/v) Triton X- 100 (Sigma)] were added and the mixture was incubated for 15 min at 22 °C to allow pre-binding of the test compounds to the enzyme before the start of the kinase reaction. Then the kinase on was started by the addition of 3 ul of a solution of adenosine-tri-phosphate (ATP, 16.7 uM => final conc. in the 5 ul assay volume is 10 uM) and substrate (1.67 uM => final conc. in the 5 ul assay volume is 1 uM) in assay buffer and the resulting e was incubated for a reaction time of 60 min at 22 °C. The tration of Akt1 in the assay was adjusted ing of the activity of the enzyme lot and was chosen appropriate to have the assay in the linear range, typical enzyme concentrations were in the range of about 0.05 ng/ul (final conc. in the 5 ul assay volume).

The on was stopped by the addition of 5 ul of a solution of HTRF detection reagents (200 nM streptavidine-XL665 [Cisbio] and 1.5 nM anti-phosho-Serine antibody pore, cat. # 35-001] and 0.75 nM LANCE Eu-W 1024 |abe|ed anti- mouse IgG dy [Perkin Elmer]) in an aqueous EDTA-solution (100 mM EDTA, 0.1 % (w/v) bovine serum albumin in 50 mM HEPES/NaOH pH 7.5).

The resulting mixture was incubated 1 h at 22°C to allow the binding of the y|ated phosphorylated peptide to the streptavidine-XL665 and the antibodies. Subsequently the amount of phosphorylated substrate was evaluated by measurement of the resonance energy transfer from the anti- mouse-lgG-Eu-Chelate to the streptavidine-XL665. Therefore, the fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm was measured in a HTRF reader, e.g. a Rubystar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665 nm and at 622 nm was taken as the measure for the amount of orylated substrate. The data were normalised (enzyme reaction without inhibitor = 0 % inhibition, all other assay components but no enzyme = 100 % inhibition). Normally test compound were tested on the same iter plate at 10 different concentrations in the range of 20 uM to 1 nM (20 uM, 6.7 uM, 2.2 uM, 0.74 uM, 0.25 uM, 82 nM, 27 nM, 9.2 nM, 3.1 nM and 1 nM, dilution series prepared before the assay at the level of the 100fo|d conc. stock solutions by serial 1 :3 dilutions) in duplicate values for each concentration and |C50 values were calculated by a 4 parameter fit using an in-house software.

Biological Assay 2.0: Akt2 kinase assay Akt2 inhibitory activity of compounds of the present invention was quantified employing the Akt2 TR-FRET assay as described in the following paragraphs.

His-tagged human recombinant kinase full-length Akt2 expressed in insect cells and activated by PDK1 was purchased form Invitrogen (part number PV 3975).

As ate for the kinase reaction the biotinylated peptide biotin-Ahx- KKLNRTLSFAEPG minus in amide form) was used which can be purchased e.g. from the company Biosynthan GmbH (Berlin-Buch, Germany).

For the assay 50 n1 of a 100fo|d concentrated solution of the test compound in DMSO was pipetted into a black low volume 384we|| microtiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 ul of a solution of Akt2 in assay buffer [50 mM TRIS/HCI pH 7.5, 5 mM MgC12, 1 mM threitol, 0.02% (v/v) Triton X- 100 (Sigma)] were added and the mixture was incubated for 15 min at 22 °C to allow pre-binding of the test compounds to the enzyme before the start of the kinase reaction. Then the kinase reaction was started by the on of 3 ul of a solution of adenosine-tri-phosphate (ATP, 16.7 uM => final conc. in the 5 ul assay volume is 10 uM) and ate (1.67 uM => final conc. in the 5 ul assay volume is 1 uM) in assay buffer and the resulting mixture was incubated for a reaction time of 60 min at 22 °C. The concentration of Akt2 in the assay was adjusted depending of the ty of the enzyme lot and was chosen appropriate to have the assay in the linear range, typical enzyme trations were in the range of about 0.2 ng/ul (final conc. in the 5 ul assay ).

The reaction was stopped by the addition of 5 ul of a solution of HTRF detection reagents (200 nM streptavidine-XL665 [Cisbio] and 1.5 nM hosho-Serine antibody [Millipore, cat. # ] and 0.75 nM LANCE Eu-W 1024 labeled anti- mouse IgG antibody [Perkin Elmer]) in an aqueous EDTA-solution (100 mM EDTA, 0.1 % (w/v) bovine serum albumin in 50 mM HEPES/NaOH pH 7.5).

The resulting mixture was incubated 1 h at 22°C to allow the binding of the biotinylated phosphorylated peptide to the streptavidine-XL665 and the antibodies. Subsequently the amount of phosphorylated substrate was evaluated by measurement of the resonance energy transfer from the anti- mouse-lgG-Eu-Chelate to the streptavidine-XL665. Therefore, the fluorescence ons at 620 nm and 665 nm after excitation at 350 nm was measured in a TR-FRET reader, e.g. a Rubystar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665 nm and at 622 nm was taken as the measure for the amount of phosphorylated substrate. The data were normalised (enzyme reaction without inhibitor = 0 % inhibition, all other assay components but no enzyme = 100 % inhibition). Normally test compound were tested on the same microtiter plate at 10 different concentrations in the range of 20 uM to 1 nM (20 uM, 6.7 uM, 2.2 uM, 0.74 uM, 0.25 uM, 82 nM, 27 nM, 9.2 nM, 3.1 nM and 1 nM, on series ed before the assay at the level of the 100-fold conc. stock solutions by serial 1:3 dilutions) in ate values for each concentration and IC50 values were calculated by a 4 parameter fit using an in-house software.

Preferred compounds of the present invention show in either the Akt1 or Akt2 kinase assay: median |C50< 5 uM or greater than 50% tion at 5 uM, more preferably, median IC50 < 0.5 uM or greater than 50% inhibition at 0.5 uM, even more preferably, median |C50 S 0.1 uM or greater than 50% inhibition at 0.1 uM.

The following Table gives selected data for selected Examples of the present invention. mAkt1 median |C5o (nM) Akt2 median |C5o (nM) 170,0 380,0 2 65,0 97,0 3 120,0 70,0 4 85,0 190,0 5,2 18,0 — 4,2 80,0 7 6,9 9,7 8 450,0 400,0 9 3,9 18,0 2,6 4,1 130,0 110,0 21,0 38,0 2012/056300 Example Akt1 median |C5o (nM) Akt2 median |C5o (nM) 13 78,0 42,0 14 9,8 65,0 4,4 56,0 160,0 160,0 43,0 92,0 86,0 53,0 ,0 42,0 120,0 170,0 73,0 130,0 8,0 18,0 1200,0 190,0 ,0 81,0 190,0 160,0 6,3 10,0 ,0 29,0 ,0 5,4 56,0 78,0 51,0 58,0 48,0 140,0 3700,0 3300,0 690,0 Not tested 3,9 14,0 350,0 1200,0 17,0 54,0 580,0 510,0 370,0 140,0 38,0 160,0 1700,0 1400,0 33,0 66,0 20000,0 20000,0 2012/056300 Example Akt1 median |C5o (nM) Akt2 median |C5o (nM) 43 36,0 110,0 44 190,0 310,0 1200,0 6600,0 110,0 85,0 220,0 350,0 180,0 610,0 68,0 120,0 44,0 27,0 42,0 81,0 26,0 15,0 9,2 2,4 12,0 35,0 45,0 56,0 6,6 16,0 ,0 29,0 110,0 280,0 65,0 110,0 m 7,2 24,0 4,1 3,7 16,0 62,0 46,0 120,0 4,8 12,0 3,1 2,6 51,0 180,0 58,0 96,0 21,0 66,0 310,0 750,0 130,0 110,0 11,0 20,0 310,0 580,0 Example Akt1 median |C5o (nM) Akt2 median leo (nM) 73 4,3 43,0 96,0 120,0 21,0 100,0 11,0 23,0 ,0 61,0 32,0 230,0 79 2000,0 2800,0 80 96,0 610,0 Cellular Assays 3.0: p-AKT1/2/3-S473, -T308, and p-4E-BP1-T70 assays The molecular ism of action was investigated in a set of experiments to assess the inhibition of the Pl3K-AKT-mTOR pathway in responsive cell lines such as KPL-4 breast tumour cell line (PIKBCA'11047R!HER2O/E and hormone independent). The o-substrates of Pl3K-AKT-mTOR axis were used as the read-outs to reflect pathway inhibition. Cells were seeded at 60-80% confluency per well in 96-well cell culture . After overnight incubation at 37°C 5% C02, cells were treated with compounds and vehicle at 37°C for 2 hours. Thereafter, cells were lysed in 150ul lysis buffer and the levels of phospho-AKT at T308 and S473 and p-4E-BP1 at T70 sites were determined with the corresponding AlphaScreen® SureFire® assay kits (Perkin Elmer: 4E- BP1 Assay Kit Cat # TRG4E281 OK; Akt 1/2/3 p-Ser 473 #TGRA4S500 and Akt 1/2/3 p-Thr 308 #TGRA38500 as well as IgG detection Kit #6760617M) as described in the manuals. All ements where at least done in duplicates and confirmed by independent repetition. atively pAKT-S473 was measured using the "Akt Duplex" of the MULTI- SPOT® Assay System (Fa. Meso Scale Discovery, Cat# N41 1OOB-1) following cturers instructions. Each assay used 20ug of protein extract and measured total AKT and p-AKT content simultaneously in one well. All measurements where at least done in duplicates and confirmed by independent tion. Values for P-AKT are expressed as percentage of P-AKT level compared to total-AKT content of the extracts.

The following Table gives ed data for selected Examples of the present invention.

Example pAKT-S743 median P4EBP1-T70 median IC50 (nM) IC50 (nM) 1 160,0 Not tested 2 310,0 2100,0 360,0 4500,0 610,0 2400,0 0,9 35,0 n 210,0 1300,0 7 27,0 1300,0 8 >10000,0 >10000,0 9 36,0 690,0 2,4 28,0 11 14,0 160,0 52,0 260,0 82,0 660,0 220,0 320,0 590,0 1700,0 520,0 2500,0 12,0 430,0 180,0 710,0 390,0 5100,0 520,0 1500,0 420,0 1700,0 0,3 23,0 1400,0 2900,0 200,0 500,0 90,0 550,0 0,9 90,0 36,0 480,0 6,2 210,0 1300,0 2012/056300 Example pAKT-S743 median P4EBP1-T70 median IC50 (nM) IC50 (nM) 400,0 2500,0 1800,0 4300,0 160,0 2200,0 2900,0 Not tested 3,1 150,0 190,0 1700,0 26,0 1600,0 81,0 2500,0 ,0 530,0 280,0 7500,0 2000,0 6100,0 >10000,0 >10000,0 120,0 2600,0 96,0 1600,0 800,0 380,0 >10000,0 >10000,0 430,0 300,0 140,0 96,0 42,0 29,0 8,0 41,0 450,0 2000,0 590,0 1200,0 2,1 9,9 200,0 1000,0 690,0 1600,0 680,0 1800,0 570,0 360,0 250,0 1800,0 1000,0 10000,0 Example pAKT-S743 median -T70 median IC50 (nM) IC50 (nM) 11,0 1000 m 1,0 8100,0 0,5 2,0 0,4 35,0 3,8 0,3 0,9 84,0 1,4 22,0 17,0 180,0 >10000,0 >10000,0 3,7 5300,0 250,0 4400,0 ,7 2400,0 92,0 10000,0 1000,0 590,0 230,0 1700,0 450,0 1200,0 230,0 1500,0 120,0 0400 77 460,0 1400,0 78 92,0 580,0 79 210,0 910,0 80 190,0 9800,0 Biological Assay 4.0: Tumor cell proliferation assays Compounds were tested in a cell-based assay that measures the capacity of the compounds to inhibit tumour cell proliferation ing a 72h drug exposure.

Cell viability is determined using CeIITiter-Glow® (CTG, Promega, cat# G7571/2/3). The ter-Glo® Luminescent Cell Viability Assay is a homogeneous method to determine the number of viable cells in culture.

Detection is based on using the |uciferase reaction to measure the amount of ATP from viable cells. The amount of ATP in cells correlates with cell viability.

Within minutes after a loss of membrane integrity, ce||s lose the ability to synthesize ATP, and endogenous ATPases destroy any remaining ATP; thus the levels of ATP fall precipitously.

Cells were plated at 3000-5000 cells/well (depending on the cell lines) in 90 uL growth medium on MTPs (Coming; #3603, black plate, clear flat bottom). For each cell line assayed, cells were plated onto a separate plate for determination of fluorescence at t = 0 hour and t = 72 hour time points. Following overnight tion at 37 oC, chemiluminescence values for the t = 0 samples were determined after adding 10u| medium and 100ul CTG solution according to manufacture protocol. Plates for the t = 72 hour time points were treated with compounds d into growth medium at ten times final concentration added in 10uL to the cell culture plate. Cells were then ted for 72 hours at 37 0C. uminescence values for the t = 72 hour samples were ined. For data analysis, briefly, data from 24h plate where used to reflect 100% inhibition of growth ("Ci") and DMSO control for uninhibited growth ("C0") and analyzed using MTS software package for IC50 and Hill coefficient. Experiments were controlled using a reference nd as standard.

Preferred compounds of the present invention show in this assay an inhibition of cell growth of cell lines such as the KPL-4 breast cancer cell line MCF-7 breast tumour cell line ( PIK3CAE542K?E545K, hormone dependent) and LNCaP te tumour cell line with a median IC50 of < 10 uM, more preferably, median IC50 S 1 pM.

The following Table gives selected data for selected Examples of the present invention.

Example KLP-4 median MCF-7 median IC50 (nM) IC50 (nM) 1 1800,0 600,0 2 1700,0 1700,0 3 1700,0 1800,0 e KLP-4 median MCF-7 median IC50 (nM) IC50 (nM) >10000,0 >10000,0 770,0 340,0 49,0 39,0 630,0 470,0 2000,0 1800,0 1100,0 32 Not tested Not tested 33 Not tested Not tested WO 36776 KLP-4 median MCF-7 median IC50 (nM) IC50 (nM) 740,0 >10000,0 >10000,0 8400,0 >10000,0 >10000,0 2800,0 4200,0 6200,0 6700,0 2000,0 1900,0 >10000,0 >10000,0 1500,0 2100,0 >10000,0 >10000,0 Not tested Not tested 1500,0 73,0 33,0 56,0 Not tested Not tested Example KLP-4 median MCF-7 median IC50 (nM) IC50 (nM) 2500,0 980,0 Not tested Not tested 1500,0 680,0 10000,0 1500,0 2600,0 940,0 2000,0 780,0 2200,0 3000,0 1800,0 2000,0 2100,0 2000,0 1800,0 940,0 1700,0 Not tested Not tested 10000,0 10000,0 10000,0 10000,0 Example 5.0 — CacoZ permeability assay Caco-2 cells (purchased from DSMZ Braunschweig, Germany) were seeded at a density of 4.5 x 104 cell per well on 24 well insert , 0.4 um pore size, and grown for 15 days in DMEM medium supplemented with 10% fetal bovine serum, 1% GIutaMAX (100x, GIBCO), 100 U/ml penicillin, 100ug/ml streptomycin (GIBCO) and 1% non essential amino acids (100 x). Cells were ined at 37°C in a humified 5% C02 atmosphere. Medium was changed every 2-3 day. Before running the permeation assay, the culture medium was replaced by a FCS-free carbonate transport puffer (pH 7.2) For assessment of monolayer integrity the pithelial electrical resistance (TEER) was measured. Test compounds were predissolved in DMSO and 2012/056300 added either to the apical or basolateral compartment in final concentration of 2 uM. Before and after 2h incubation at 37°C samples were taken from both compartments. Analysis of compound t was done after precipitation with methanol by LC/MS/MS is. Permeability (Papp) was calculated in the apical to basolateral (A —> B) and basolateral to apical (B —> A) directions. The apparent permeability was calculated using following equation: Papp = (Vr/Po)(1/S)(P2/t) Where Vr is the volume of medium in the receiver chamber, P0 is the measured peak area of the test drug in the donor chamber at t=0, S the surface area of the monolayer, P2 is the measured peak area of the test drug in the acceptor chamber after 2h of incubation, and t is the incubation time. The efflux ratio basolateral (B) to apical (A) was calculated by dividing the Papp B-A by the Papp A-B. In addition the compound recovery was calculated. As assay control reference compounds were analyzed in parallel. e 6.0 — in vivo rat pharmacokinetics For in vivo pharmacokinetic experiments test compounds were administered to male Wistar rats intravenously at doses of 0.5 to 1 mg/kg and astral at doses of 1 to 10 mg/kg formulated as solutions using solubilizers such as PEG400 in well-tolerated amounts.

For pharmacokinetics after intravenous administration test compounds were given as iv bolus and blood samples were taken at 2 min, 8 min, 15 min, 30 min, 45 min, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h after dosing. Depending on the expected half-life additional samples were taken at later time points (e.g. 48 h, 72 h). For pharmacokinetics after intragastral administration test compounds were given intragastral to fasted rats and blood samples were taken at 5 min, 15 min, 30 min, 45 min, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h after dosing. Depending on the expected half-life additional samples were taken at later time points (e.g. 48 h, 72 h). Blood was collected into Lithium-Heparintubes (Monovetten® , Sarstedt) and fuged for 15 min at 3000 rpm. An t of 100 uL from the supernatant (plasma) was taken and precipitated by on of 400 uL cold acetonitrile and frozen at -20 °C over night. Samples were subsequently thawed and fuged at 3000 rpm, 4°C for 20 minutes. Aliquots of the supernatants were taken for analytical testing using an Agilent 1200 HPLC-system with S detection. PK parameters were calculated by non-compartmental analysis using a PK calculation software.

PK parameters derived from concentration-time profiles after i.v.: CLplasma: Total plasma clearance of test nd (in L/kg/h); CLblood: Total blood clearance of test nd: CLplasma*Cp/Cb (in L/kg/h) with Cp/Cb being the ratio of concentrations in plasma and blood. PK parameters calculated from concentration time profiles after i.g.: Cmax: Maximal plasma concentration (in mg/L); Cmaxnorm: Cmax divided by the administered dose (in kg/L); Tmax: Time point at which Cmax was observed (in h). Parameters calculated from both, iv and i.g. concentration-time profiles: m: Area under the concentration-time curve from t=0h to infinity (extrapolated) divided by the administered dose (in kg*h/L); AUC(0-tlast)norm: Area under the tration- time curve from t=0h to the last time point for which plasma concentrations could be measured divided by the administered dose (in kg*h/L); t1/2: terminal half-life (in h); F: oral bioavailability: m after intragastral administration divided by AUCnorm after intravenous administration (in %).

The person d in the art will be aware of methods to show in vivo efficacy of anti-cancer compounds. By way of illustration, the following example describes methods of quantifying the in vivo efficacy in a mouse xenograft model. The skilled person will be able to apply such principles to derive models from alternative tumor material.

Example 7.0 In vivo xenograft mechanism of action study To demonstrate that nds act in tumours by the anticipated mode of action phosphorylation of the AKT n was investigated in KPL-4 breast tumours treated once with 50 mg/kg compound.

To this extent KPL-4 human breast tumours were xenografted onto athymic nude mice. KPL-4 tumour cells were cultivated ing to ATCC protocols in recommended media contained 10% FCS and harvested for transplantation in a 2012/056300 subconfluent (70%) state. 3 x 106 tumour cells suspended in 50% Matrigel were aneously implantated into the inguinal region of female mice. Tumours were allowed to grow to the predetermined size of 60-80 mm2. When the tumours were approximately in size, the animals were randomized to ent and control groups (groups size: 9 animals) and treatment was started. Animals were treated once with 50 mg/kg compound or vehicle per oral administration (p.o.) carried out via a gastric tube. Treatment of each animal was based on dual body . At 2, 5 and 24 hours post ent 3 animals each were sacrificed and the KPL-4 tumours d. Tumour samples of approximately 5x5x5 mm were lysed on ice in MSD lysis buffer in the presence of protease and phosphatase inhibitors using Tissue Lyzer (Qiagen, Germany). The levels of p-AKT S473 in extracts from tumour tissue were analysed in an ELISA based assay. This assay is based on the "Akt Duplex" of the MULTl-SPOT® Assay System (Fa. Meso Scale ery, Cat# N41 1008-1) following manufacturers instructions. Each assay used 20ug of protein extract and measured total AKT and p-AKT content simultaneously in one well. All measurements where at least done in duplicates and med by independent repetition.

Values for P-AKT are expressed as percentage of P-AKT level compared to total-AKT content of the extracts. Vehicle treated tumours were analyzed to determine the basal level of P-AKT in this model and used as a normalization control to determine the % P-AKT relative to vehicle levels.

Preferred compounds of the present invention show in this assay: relative to vehicle levels P-AKT < 30 % at 2 hours post ent, more preferably at 5 hours post ent, even more preferably at 24 hours post treatment.

Example 7.1 In vivo xenograft efficacy study To determine the therapeutic efficacy and tolerability of compounds, tumour growth of KPL-4 breast tumours xenografted onto nude mice may be observed.

Mice were treated either with vehicle or compounds.

To this extent KPL-4 xenografts were established as described above. Tumours were allowed to grow to the predetermined size of 25 — 35 mm2. When the tumours were approximately in size, the animals were randomized to treatment and control groups (groups size: 8 animals) and treatment was started.

Treatment of each animal was based on individual body weight and oral stration (p.o.) was d out via a gastric tube. The oral ation volumes were 10 ml/kg for mice. Mice were treated once daily with 50 mg/kg compounds.

Tumour response was assessed by determination of the tumour area ct of the longest diameter and its perpendicular) using a calliper. The animal body weight was monitored as a measure for treatment-related toxicity. Measurement of tumour area and body weight were performed 2—3 times weekly. Statistical analysis was assessed using the SigmaStat software. A one way analysis of ce was performed, and differences to the control were compared by a pair-wise comparison procedure (Dunn’s method). T/C ratios (Treatment/ Control) were calculated with final tumour weights at study end.

Claims (5)

Claims 1.

1. A nd of formula (I) in which R1 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(O)OR8, C(O)(1-6C-alkyl), NHC(O)(1-6C-alkyl), NHS(O)2R11, NHC(O)NHR11 ,- S(O)nGC-alkyl, -S(O)2NR5R6 or a group selected from 1-6C-alkyl, 1- GC-alkoxy, 3-7C-cycloalkyl, aryl, heteroaryl, -(1-6C-alky|)-ary|, -(1-6C- 10 alky|)-heteroary|, -O-(3-7C-cycloa|kyl), -O-ary|, -O-(3-7C-heterocyclyl), -O- heteroaryl, -O-(1-GC-a|kyl)-heteroaryl, -O-(1-GC-alkyl)-(3-7C-heterocyclyl), -O-(1-6C-a|kyl)-aryl, 2—6C-alkenyl, 2—6C-alkynyl, wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from: 15 hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, lkoxy, -NR8R9, cyano, -C(O)NR8R9, -C(O)OR10, )R11, -NHC(O)NHR11, - NHS(O)2R11, cloalkyl, eterocyclyl, aryl, R2 is en, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(O)OR8, C(O)(1-6C-alkyl), NHC(O)(1-6C-alkyl), NHS(O)2R11, NHC(O)NHR11 ,- 20 S(O)nGC-alkyl, NR5R6 or a group selected from 1-6C-alkyl, 1- GC-alkoxy, 3-7C-cycloalkyl, aryl, heteroaryl, -alky|)-ary|, -(1-6C- alky|)-heteroary|, -O-(3-7C-cycloa|kyl), -O-ary|, -O-(3-7C-heterocyclyl), -O- heteroaryl, -O-(1-GC-a|kyl)-heteroaryl, -O-(1-GC-alkyl)-(3-7C-heterocyclyl), -O-(1-6C-a|kyl)-aryl, 2—6C-alkenyl, 2—6C-alkynyl, 25 wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from: hydroxy, n, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy, -NR8R9, cyano, -C(O)NR8R9, R10, -NHC(O)R11, -NHC(O)NHR11, - NHS(O)2R11, 3-7C-heterocyclyl, aryl, R3 is hydrogen, hydroxy, NR5R6, n, cyano, CO(NR8R9), C(O)OR8, C(O)(1-6C-alkyl), NHS(O)2R11, NHC(O)NHR11 - S(O)n6C-alkyl, - S(O)2NR5R6 or a group selected from lkyl, 1-GC-alkoxy 3-7C- cycloalkyl, aryl, aryl, -(1-6C-alkyl)-aryl, -(1-6C-alkyl)-heteroaryl, -O- (3-7C-cycloalkyl), -O-ary|, -O-(3-7C-heterocyc|y|), -O-heteroary|, -O-(1- 6C-alkyI)-heteroaryl, -O-(1-GC-a|kyl)-(3-7C-heterocyc|y|), -O-(1-GC-alkyl)- 10 aryl, NHC(O)(1-6C-alkyl), 2—6C-alkenyl, 2—6C-alkynyl, wherein said group being optionally substituted, one or more times, identically or differently, with a tuent selected from: hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy, -NR8R9, cyano, -C(O)NR8R9, -C(O)OR10, -NHC(O)R11, -NHC(O)NHR11, - 15 NHS(O)2R11, 3-7C-heterocyclyl, aryl, R4 is phenyl which is optionally substituted one, two or three times, identically or differently, with a halogen atom; R5 is hydrogen, 1-6C-alkyl, R6 is hydrogen, 1-6C-alkyl, 20 R8 is hydrogen, 1-6C-alkyl which optionally is substituted with y, R9 is hydrogen, 1-6C-alkyl, R10 is hydrogen, 1-6C-alkyl, R11 is hydrogen, 1-6C-alkyl, X, Y is CH2; 25 n is O, 1, 2; or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or isomer. 30

2. The compound according to claim 1 R1 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(O)OR8, C(O)(1-3C-alkyl), NHC(O)(1-6C-alkyl), NHS(O)2R11, NHC(O)NHR11 ,- S(O)nBC-alkyl, -S(O)2NR5R6 or a group selected from 1-BC-alkyl, 1- BC-alkoxy, 3-GC-cycloalkyl, aryl, aryl, -alkyl)-aryl, -(1-BC- alkyl)-heteroaryl, -O-(3-GC-cycloalkyl), -O-aryl, -O-(3-GC-heterocyclyl), -O- heteroaryl, -O-(1-BC-alkyl)-heteroaryl, -O-(1-BC-alkyl)-(3-6C-heterocyclyl), -O-(1-BC-alkyl)-aryl, 2-BC-alkenyl, 2-BC-alkynyl, wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from: hydroxy, halogen, 1-BC-alkyl, 1-3C-haloalkyl, lkoxy, -NR8R9, cyano, R8R9, -C(O)OR10, -NHC(O)R11, -NHC(O)NHR11, - 10 NHS(O)2R11, cloalkyl, 3-6C-heterocyclyl, aryl, R2 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(O)OR8, C(O)(1-3C-alkyl), NHC(O)(1-3C-alkyl), NHS(O)2R11, NHC(O)NHR11 ,- S(O)nBC-alkyl, -S(O)2NR5R6 or a group selected from 1-BC-alkyl, 1- BC-alkoxy, 3-GC-cycloalkyl, aryl, heteroaryl, -(1-BC-alkyl)-aryl, - 15 alkyl)-heteroaryl, -O-(3-GC-cycloalkyl), -O-aryl, -O-(3-GC-heterocyclyl), -O- heteroaryl, -O-(1-BC-alkyl)-heteroaryl, -O-(1-BC-alkyl)-(3-6C-heterocyclyl), -O-(1-BC-alkyl)-aryl, 2-BC-alkenyl, 2-BC-alkynyl, wherein said group being optionally substituted, one or more times, cally or differently, with a substituent selected from: 20 hydroxy, halogen, lkyl, 1-3C-haloalkyl, 1-BC-alkoxy, -NR8R9, cyano, -C(O)NR8R9, -C(O)OR10, -NHC(O)R11, -NHC(O)NHR11, - NHS(O)2R11, 3-GC-heterocyclyl, aryl, R3 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(O)OR8, C(O)(1-3C-alkyl), NHS(O)2R11, NHC(O)NHR11 - S(O)n3C-alkyl, - 25 S(O)2NR5R6 or a group selected from 1-BC-alkyl, lkoxy 3 lkyl, aryl, heteroaryl, -(1-BC-alkyl)-aryl, -(1-BC-alkyl)-heteroaryl, -O- (B-GC-cycloalkyl), -O-aryl, -O-(3-6C-heterocyclyl), eroaryl, -O-(1- BC-alkyl)-heteroaryl, -O-(1-BC-alkyl)-(3-6C-heterocyclyl), -O-(1-3C-alkyl)- aryl, NHC(O)(1-BC-alkyl), 2-BC-alkenyl, 2-BC-alkynyl, 30 wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from: hydroxy, halogen, 1-BC-alkyl, 1-3C-haloalkyl, 1-BC-alkoxy, -NR8R9, cyano, -C(O)NR8R9, -C(O)OR10, -NHC(O)R11, -NHC(O)NHR11, - NHS(O)2R11, 3-GC-heterocyclyl, aryl, R4 is phenyl which is optionally substituted one, two or three times, cally or differently, with a halogen atom; R5 is hydrogen, 1-BC-alkyl, R6 is hydrogen, 1-BC-alkyl, R8 is hydrogen, 1-3C-alkyl which optionally is tuted with hydroxy, R9 is hydrogen, 1-BC-alkyl, 10 R10 is en, 1-BC-alkyl, R11 is hydrogen, 1-BC-alkyl, X, Y isCHz n is O, 1, 2; or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt 15 of said N-oxide, tautomer or stereoisomer.

3. The compound ing to claim 1 20 R1 is hydrogen, hydrogen, y, NR5R6, CO(NR8R9), 8, NHC(O)(1-GC-alkyl), NR5R6 or a group selected from 1-GC-alkyl, 3-7C- cycloalkyl, aryl, heteroaryl, 1-4C-alkoxy, wherein said group being optionally substituted, one or more times, cally or differently, with a tuent selected from: halogen, 1-GC-alkyl, 1-GC-alkoxy, -C(O)OR10, 25 3cycloalkyl, aryl, R2 is hydrogen, 1-6C-alkyl, R3 is hydrogen, hydroxy, NR5R6, halogen, ,CO(NR8R9), C(O)OR8, C(O)(1- 6C-alkyl), NHS(O)2R11, S(O)nGC-alkyl, or a group selected from 1 alkyl, 1-6C-alkoxy aryl, NHC(O)(1-6C-alkyl), 2—6C-alkenyl, wherein said 30 group being optionally substituted, one or more times, identically or differently, with a substituent selected from: halogen, -C(O)OR10, R4 is phenyl R5 is hydrogen, R6 is hydrogen, R8 is hydrogen, 1-4C-alkyl, which optionally is substituted with hydroxy, R9 is hydrogen, 1-4C-alkyl, R10 is, 1-4C-alkyl, R11 is 1-4C-alkyl, X, Y iS CH2 n is O, 1, 2; or an N-oxide, a salt, a tautomer or a isomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

4. A nd according to claim 1 wherein R1 is hydrogen, hydroxyl, amino, methoxy, ethoxy, , pyridineyl, 15 pyridineyl, pyrazolyl, 1-methyl-pyrazolyl, imidazoleyl, methyl, propyl, -O-(CH2)-O-CH3, -O-CH2—phenyl, -cyclopropyl, -C(O)OCH3, -C(O)- NHCHs, -C(O)-NH2, 4-fluoro-phenyl, -(CH2)2—C(O)OCH3, cyclopropyl, -NH- C(O)CH3, R2 is hydrogen, methyl, 20 R3 is hydrogen, hydroxy, amino, , ethyl, methoxy, ethoxy, -O-CH2— C(O)OCH3, -S—CH3, -SOz-CH3, bromine, chlorine, trifluoromethyl, C(O)NH2, COOH,C(O)OCH3, C(O)OCH20H3, C(O)NH2, C(O)NHCHs, C(O)N(CH3)2, C(O)NH(CH2)2—OH, -CH=CH2, 4-fluoro-phenyl, NHC(O)CH3, CF3, NH-SOz-CHs, C(O)CH3, 25 R4 is phenyl X, Y is CH2 or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer. 30

5. A nd according to claim 1 selected from the group consisting of