COMPOUNDS USEFUL AS CSF1 MODULATORS

[0001] This invention relates to novel compounds and to pharmaceutical compositions comprising the novel compounds. More specifically, the invention relates to compounds useful as Colony Stimulating Factor 1 Receptor (cFMS) modulators (e.g. cFMS inhibitors). This invention also relates to processes for preparing the compounds, uses of the compounds in treatment and methods of treatment employing the compounds. Specifically, the invention relates to the use of the compounds for the treatment of cancer and autoimmune diseases.

BACKGROUND

[0002] "The evidence for a role of the CSF-1 , IL-34, cFMS axis in the initiation, growth and metastatic spread of cancer is now extensive" Burns and Wilks ("c-FMS inhibitors: a patent review", Expert Opin Ther Pat. 2011 ; 21 (2): 147-165)

[0003] Colony Stimulating Factor 1 Receptor (cFMS), also known as CD1 15, CSF-1 R, FMS, MCSFR, is a key receptor involved in the modulation and/or maintenance of cell types of the monocyte/ macrophage lineage (which include osteoclasts in the bone). There are two ligands for cFMS, Colony Stimulating Factor 1 (CSF-1) and Interleukin 34 (IL-34). Both ligands appear to bind to the same receptor although the ligands themselves do not have appreciable sequence homology and appear to have evolved independently. IL-34's role appears to be in the maintenance of peripheral macrophages, with CSF-1 more involved in modulation/maintenance in tissues. It has been shown however that IL-34 may substitute for CSF-1 in RANKL stimulated osteoclast formation meaning that only blockade of both cytokines, either via small molecule inhibition of the phosphorylation site or a suitable antibody at the receptor site, would prove effective in inhibiting osteoclast formation.

[0004] In tissues, GM CSF has an effect on the impact of CSF-1 on the development of macrophage. In the presence of GM CSF and CSF-1 , macrophages adopt the M1 phenotype

(responsive to Type 1 inflammatory cytokines and microbial PAMPs such as LPS). In the absence of GM CSF, macrophages adopt the M2 phenotype (immunomodulatory/immunosuppressive, expressing high levels of I L 10) . In tumours, macrophages represent the highest proportion of the lymphocytic infiltrate and these macrophages are predominantly of the M2 phenotype and potentially contribute to the tumours' strategies for avoiding detection by the immune system. In addition, CSF-1 and cFMS are over-expressed in a number of tumours including pancreatic, Hodgkin's lymphoma, AML, breast, cervical, endometrial and ovarian where they may also have an autocrine role.

[0005] In bone, osteoclasts express cFMS and osteoblasts CSF1 and the CSF1/cFMS axis is involved along with RANKL in the dynamics of bone metabolism. Metastatic tumour cells that express cFMS can be recruited into the bone as part of this dynamic metabolism.

[0006] Inhibition of cFMS has the effect of reducing macrophage population in the tumour environment and is also able to 're-educate' the tumour associated macrophages from the pro- tumourogenic M2 phenotype and potentially recruit them as suppressors of tumourigenesis (Pyonteck, S. M., et. a/., Nature Medicine, 2013, 1264-1275). Inhibition of cFMS in cancers where elevated levels of CSF-1 expression has caused progression of the disease into the bone, caused bone erosion, causes the reduction in number of tumour associated macrophages, and therefore a reduction in the number osteoclasts, in the tumour environment which reduces bone damage in these indications.

[0007] The presence of large numbers of macrophages at sites of inflammation, such as the rheumatoid synovium, immune-mediated nephritis, inflammatory bowel disease, coronary disease, sarcoidosis and chronic obstructive pulmonary disease, places mediators of macrophage function, such as CSF-1 , at the very heart of therapeutic intervention in a wide range of inflammatory diseases. Macrophages at the site of inflammation are sources of pro-inflammatory cytokines such as TNF-a and ΙΙ_-1 β. Elevated levels of circulating CSF-1 have been reported in many autoimmune diseases, including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).

[0008] RA is an autoimmune chronic inflammatory disease characterised by bone and cartilage destruction that is mediated by bone-resorbing osteoclasts which occurs in around 1 % of the adult population worldwide. Elevated levels of CSF-1 have been observed in the synovial fluid of RA patients and synovial fibroblasts from RA patients produce high levels of CSF-1 . As CSF-1 plays an important role in the development of osteoclasts this suggests an important role for CSF-1 in joint degradation in RA.

[0009] Given that CSF-1 is the primary regulator of the survival, proliferation and differentiation of cells of the monocyte/macrophage lineage and the clear role of macrophages play in the recruitment of osteoclasts resulting in joint destruction, fuelled by autocrine and paracrine signalling of CSF-1 and RANKL, inhibition of CSF-1 's receptor - cFMS - seems an attractive option in the treatment of RA. In particular, inhibition of cFMS offers a promising method of treating bone erosion in RA by inhibiting osteoclast formation and growth and therefore reducing their ability to cause bone and joint damage. Inhibition of the CSF-1 cytokine itself would not be a suitable option for the inhibition of joint degradation in RA for the reasons outlined below.

[0010] cFMS is a receptor tyrosine kinase that has two known ligands - CSF-1 and the recently (2008) discovered IL-34. Following its discovery, numerous reports have appeared which describe elevated levels of IL-34 in patients with RA and other inflammatory diseases. It has also been shown that IL-34 is able to activate cFMS in a complimentary manner to CSF-1 , meaning that in the event of CSF-1 inhibition IL-34 is able to activate cFMS and support osteoclast differentiation in a similar manner as CSF-1 . Differing reports of the effects of two anti-cFMS MAbs have suggested that binding to the receptor site of cFMS may result in the blockade of only one of the two cytokines resulting in little or no effect in an inflammation model. In this context, using a small molecule to block the intracellular phosphorylation site offers an attractive method of blocking the activation of cFMS by both of its ligands.

[0011] Pharmascience Ltd have filed a patent application - WO 2012/135937 - which discloses inhibitors of tyrosine kinases, including platelet-derived growth factor receptor (PDGFR) and cFMS. [0012] In another application Pharmascience Ltd disclose compounds similar to those in WO 2012/135937. The compounds are disclosed as being inhibitors of tyrosine kinases, in particular members of the Tec, Src, Btk and Lck protein kinase families.

BRIEF SUMMARY OF THE DISCLOSURE

[0013] In accordance with the present inventions there is provided a compound of formula (I):

(I)

wherein

Z is -Y -(CR ^4A R ^5A )n-R ¹ or Y ² ,

Y is -NR ⁸ C(0)- or -C(0)NR ⁸ -,

Y ² is represented by -C(0)N(R ⁹ )2 wherein the two R ⁹ groups taken together form a heterocyclic ring system with the nitrogen atom to which they are attached, wherein the heterocyclic ring system is a 5 or 6 membered monocyclic ring system or a 8, 9, 10 or 1 1 membered bicyclic ring system and which is unsubstituted or substituted by 1 to 4 substituents each independently selected from: halo, -OR ^A , -NR ^A R ^B , -NR ^A C(0)R ^c , -C(0)NR ^A R ^B , -NR ^A S0 ₂ R ^c , -S0 ₂ NR ^A R ^B , - S0 ₂ R ^c , -CN, Ci- alkyl, Ci- haloalkyl and C3-6 cycloalkyl;

X is a group selected from: CR ⁰ R ¹¹ , O, S or NR ² ;

B , B ² , B ³ and B ⁴ are independently selected from CR ³ or N, such that not more than two of B , B ² , B ³ and B ⁴ are N;

R is substituted or unsubstituted: C5-10 carbocyclic and C5-10 heterocyclic, when substituted R is substituted by 1 to 4 substituents each independently selected from: halo, -OR ^A , =0, -NR ^A R ^B , -

NR ^A C(0)R ^c , -C(0)NR ^A R ^B , -NR ^A S0 ₂ R ^c , -S0 ₂ NR ^A R ^B , -S0 ₂ R ^c , -C(0)R ^c , -CN, -N0 ₂ , C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, C3-6 halocycloalkyl, C3-6 heterocycloalkyl, Ci- ₄ alkyl substituted with -OR ^A , Ci- ₄ alkyl substituted with phenyl, C3-6 heterocycloalkyl substituted with -OR ^A , phenyl, -C(0)phenyl, - C(0)CH ₂ phenyl, and -C(0)Ophenyl, -C(0)OCH ₂ phenyl;

R ² and R ³ are each independently selected from: H, Ci- ₄ alkyl and Ci- ₄ haloalkyl; R ⁴ , R ⁵ R ^4A and R ^5A are each independently selected at each occurrence from: H, halo, C1-4 alkyl, Ci- 4 haloalkyl, -OR ^A and -NR ^A R ^B ;

R ⁶ , R ⁷ , R ⁰ and R are independently selected at each occurrence from: H, halo, C1-4 alkyl, C1-4 haloalkyl, -OR ^A , -NR ^A R ^B , -NR ^A C(0)R ^c , -NR ^A S0 ₂ R ^c , -CN and C1-4 alkyl substituted with -OR ^A ;

R ⁸ is selected from: H, C1-4 alkyl and C1-4 haloalkyl;

R ² is selected from: H, C1-4 alkyl, C1-4 haloalkyl and C1-4 alkyl substituted with -OR ^A ;

R ³ is independently selected at each occurrence from: H, halo, C1-4 alkyl, C1-4 haloalkyl, -OR ^A , -CN, -NR ^A R ^B , -SR ^A , and C1-4 alkyl substituted with -OR ^A ;

m and n are each independently selected from 0, 1 , 2, 3 or 4,

R ^A and R ^B are each independently selected at each occurrence from: H, C1-4 alkyl and C1-4 haloalkyl; and

R ^c is selected from: C1-4 alkyl and C1-4 haloalkyl;

provided that m + n is 1 or more when R is unsubstituted phenyl.

[0014] The present invention also provides compounds of formula (I) and pharmaceutically acceptable salts thereof.

[0015] In an embodiment there are provided compounds of the invention provided that m + n is 1 or more when R is unsubstituted Ce-io aryl.

[0016] R may be substituted or unsubstituted: C5-10 carbocyclic and C5-10 heterocyclic, when substituted R is substituted by 1 to 4 substituents each independently selected from: halo, -OR ^A , - NR ^A R ^B , -NR ^A C(0)R ^c , -C(0)NR ^A R ^B , -NR ^A S0 ₂ R ^c , -S0 ₂ NR ^A R ^B , -S0 ₂ R ^c , -C(0)R ^c , -CN, -NO2, C1-4 alkyl, C1-4 haloalkyl, C3-6 cyclcoalkyl, C3-6 halocyclcoalkyl, C1-4 alkyl substituted with -OR ^A , C1-4 alkyl substituted with phenyl, phenyl, -C(0)phenyl, -C(0)CH ₂ phenyl, and -C(0)Ophenyl, - C(0)OCH ₂ phenyl;

[0017] In an embodiment R ⁶ , R ⁷ , R ⁰ and R are independently selected from: H, halo, C1-4 alkyl, C1-4 haloalkyl, -OR ^A , and C1-4 alkyl substituted with -OR ^A . R ^A may be as described above.

Alternatively, R ^A may be selected from: H, methyl, ethyl, isopropyl, tert-butyl and trifluoromethyl. In a preferred embodiment R ⁶ and R ⁷ are independently selected from: H, chloro, fluoro, methyl, ethyl, trifluoromethyl, trifluorethyl, -OH, -OMe, -OEt, -OCF3, -CH ₂ OH and -CH ₂ CH ₂ OH. In a preferred embodiment R ⁰ and R are independently selected from: H, chloro, fluoro, methyl, ethyl, trifluoromethyl, trifluorethyl, -OH, -OMe, -OEt, -OCF3, -CH ₂ OH and -CH ₂ CH ₂ OH.

[0018] In an embodiment R ² is selected from: H, C1-4 alkyl, C1-4 haloalkyl and C1-4 alkyl substituted with -OR ^A , wherein R ^A is selected from: H, methyl, ethyl, isopropyl, tert-butyl and trifluoromethyl. In a preferred embodiment R ² is selected from: H, methyl, ethyl, trifluoromethyl, trifluoroethyl, -CH ₂ OH and -CH ₂ CH ₂ OH. [0019] In an embodiment R ⁶ and R ⁷ are each independently selected from H or methyl. In an embodiment R ⁶ and R ⁷ are H . In an embodiment R ⁶ , R ⁷ , R ⁰ and R are each independently selected from H or methyl. In an embodiment R ⁶ , R ⁷ , R ⁰ and R are H.

[0020] In an embodiment the compound of formula (I) is a compound according to formula (I I):

[0021] In an embodiment X is CR ⁰ R ¹¹ or O. Preferably X is CH ₂ or O.

[0022] In an embodiment R ⁰ , R and R ² are each independently selected from H or methyl. Preferably, R ⁰ , R and R ² are H.

[0023] R ⁶ , R ⁷ , R ⁰ , R and R ² may all be H.

[0024] In an embodiment the compound of formula (I) is a compound according to formulae (lla) and (lib):

[0025] In an embodiment B , B ² , B ³ and B ⁴ are independently selected from CR ³ or N, wherein not more than one of B , B ² , B ³ and B ⁴ are N. In an embodiment B , B ² , B ³ and B ⁴ are CR ¹³ .

[0026] R ³ may be independently selected at each occurrence from H, halo, C1-4 alkyl, C1-4 haloalkyl, -OR ^A , -CN, and C1-4 alkyl substituted with -OR ^A . R ³ may be independently selected at each occurrence from: H, chloro, fluoro, methyl, ethyl, trifluoromethyl, trifluorethyl, -OH, -OMe, -OEt, -OCF3, -CH2OH and -CH2CH2OH . In a preferred embodiment R ³ is independently at each occurrence H, chloro, fluoro, -OMe, -CF3, or -OCF3. Opionally, R ³ is independently at each occurrence H, fluoro or -OMe,

[0027] In an embodiment one of B\ B ² , B ³ and B ⁴ is C-OMe and the remaining B , B ² , B ³ and B ⁴ are CH. In an embodiment one of B , B ² , B ³ and B ⁴ is C-F and the remaining B , B ² , B ³ and B ⁴ are CH. In an alternative embodiment B , B ² , B ³ and B ⁴ are CH.

[0028] In an embodiment the compound of formula (I) is a compound according to formulae (Ilia), (lllb) or (lllc):

[0029] In an embodiment one of B\ B ² , B ³ and B ⁴ is C-OCF3 and the remaining B , B ² , B ³ and B ⁴ are CH. In an embodiment one of B , B ² , B ³ and B ⁴ is C-CI and the remaining B , B ² , B ³ and B ⁴ are CH. In an embodiment one of B , B ² , B ³ and B ⁴ is C-CF3 and the remaining B , B ² , B ³ and B ⁴ are CH.

[0030] In an embodiment the compound of formula (I) is a compound according to formulae (llld), (llle) or (lllf):

[0031] In an embodiment the compound of formula (I) is a compound according to formulae (Ilia), (lllb), (lllc), (llld), (llle) or (lllf).

[0032] In an embodiment there is provided a compound of formulae (Ilia), (lllb) or (lllc), wherein X is CR ⁰ R or O, preferably CH ₂ or O.

[0033] In an embodiment Z is -Y -(CR ^4A R ^5A ) _n -R ¹ .

[0034] In an embodiment the compound of formula (I) is a compound according to formula (IV):

(IVa) (IVb)

[0036] In an embodiment R ⁴ , R ⁵ , R ^4A and R ^5A are each independently selected from: H, chloro, fluoro, methyl, ethyl, trifluoromethyl, -OH, -OMe, -NH2, -NHMe and -ΝΜβ2.

[0037] In an embodiment one of R ⁴ , R ⁵ , R ^4A and R ^5A is fluoro, methyl and -NH2 and the remainder are H. In an embodiment, one of R ⁴ , R ⁵ , R ^4A and R ^5A is fluoro and the remainder are H. In an embodiment, one of R ⁴ , R ⁵ , R ^4A and R ^5A is methyl and the remainder are H. In an embodiment, one of R ⁴ , R ⁵ , R ^4A and R ^5A is -NH2 and the remainder are H.

[0038] In an embodiment R ⁴ and R ⁵ are H. In an embodiment R ⁴ and R ⁵ are H and m is 1 or 2.

[0039] In an embodiment, R ^4A is fluoro and R ^5A is H. In an embodiment, R ^4A is methyl and R ^5A is H. In an embodiment, R ^4A is -NH2 and R ^5A is H. In an embodiment, R ^4A is fluoro and R ^5A is H and n is 1 or 2. In an embodiment, one of R ^4A is methyl and R ^5A is H and n is 1 or 2. In an embodiment, R ^4A is fluoro and R ^5A is -NH2 and n is 1 or 2. [0040] In a preferred embodiment m is 0, 1 or 2, optionally 1 or 2. In a particular embodiment m is 1 . In a preferred embodiment n is 0, 1 or 2, optionally 1 or 2. In a particular embodiment n is 1 . In an embodiment m and n may be selected from 0, 1 or 2.

[0041] In an embodiment m is 1 or 2 (preferably 1) and n is 0. In an alternative embodiment m is 0 and n is 1 , 2 or 3 (preferably 1 or 2). In an embodiment m is 1 or 2 (preferably 1), n is 0 and Y is - C(0)NR ⁸ -. In an alternative embodiment m is 0 and n is 1 , 2 or 3 (preferably 1 or 2) and Y is - NR ⁸ C(0)-.

[0042] In an embodiment the compound of formula (I) is a compound according to formulae (Va) or (Vb):

(Va) (Vb)

[0043] R may be selected from substituted or unsubstituted: Ce-io aryl, C5-10 heteroaryl, C5-10 cycloalkyl, C5-10 heterocycloalkyl C5-10 cycloalkylene and C5-10 heterocycloalkylene.

[0044] C5-10 cycloalkyl may represent cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0045] C5-10 cycloalkenyl may represent cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienly, cycloheptenyl, cycloheptadiene, cyclooctenyl, cyclooctadienyl, indanyl, indenyl or tetralinyl.

[0046] C5-10 heterocycloalkyl may represent tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, dioxolane, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, dioxane or tetrahydropyran,.

[0047] C5-10 heterocycloalkenyl may represent pyrroline, imidazoline, pyrazoline, oxazoline, isoxazoline, thiazoline, isothiazoline, dihydropyran, indoline, isoindoline, chromene, chromane, isochromane, dihydroquinoline, tetrahydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, dihydrobenzofuran, benzomorpholine or benzodioxolane. Optionally, C5-10 heterocycloalkylene is not dihydrobenzofuran, benzomorpholine.

[0048] Ce-io aryl may represent phenyl or napthyl. [0049] C5-10 heteroaryl may represent pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, benzoxadiazolyl and benzimidazolyl.

Optionally, C5-10 heteroaryl is not benzoxadiazolyl.

[0050] In an embodiment R is a ring selected from unsubstituted or substituted cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienly, cycloheptenyl, cycloheptadiene, cyclooctenyl, cyclooctadienyl, indanyl, indenyl, tetralinyl, tetrahydrofuran, pyrrolidine, pyrroline, imidazolidine, imidazoline, succinimide, pyrazolidine, pyrazoline, oxazolidine, oxazoline, dioxolane, isoxazolidine, isoxazoline, thiazolidine, thiazoline, isothiazolidine, isothiazoline, piperidine, morpholine, thiomorpholine, dihydrobenzofuran, benzomorpholine, piperazine, dioxane, dihydropyran, tetrahydropyran, indoline, isoindoline, chromene, chromane, isochromane, dihydroquinoline, tetrahydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, benzodioxolane phenyl, napthyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, benzoxadiazolyl and benzimidazolyl. Optionally, R is not dihydrobenzofuran, benzomorpholine or benzoxadiazolyl.

[0051] R may be selected from unsubstituted or substituted: phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, imidazolyl, pyrazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, indanyl, indolyl, indolinyl, azaindolyl, benzthiazolyl, benzodioxolane, piperidinyl, piperazinyl, morpholinyl, pyrolidinyl, cyclohexyl, tetrahydroquinoline, dihydrobenzofuran, benzomorpholine, benzoxadiazolyl and tetrahydropyranyl.

[0052] R may be selected from unsubstituted or substituted: phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, imidazolyl, pyrazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, indanyl, indolyl, indolinyl, azaindolyl, benzthiazolyl, benzodioxolane, tetrahydroquinoline,

dihydroisoquinoline, dihydrobenzofuran, benzomorpholine, benzoxadiazolyl, piperidinyl, piperazinyl, morpholinyl and pyrolidinyl.

[0053] Alternatively, R may be selected from unsubstituted or substituted: phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, indolyl, indanyl, cyclohexyl and tetrahydropyranyl.

[0054] R may be substituted by 1 to 4 substituents (optionally 1 , 2 or 3) each independently selected from: halo, -OR ^A , -NR ^A R ^B , -C(0)NR ^A R ^B , -C(0)R ^c , -CN, -NO2, C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, C1-4 alkyl substituted with -OR ^A , C1-4 alkyl substituted with phenyl, phenyl, -C(0)phenyl, - C(0)CH ₂ phenyl, -C(0)Ophenyl, and -C(0)OCH ₂ phenyl.

[0055] R may be substituted by 1 to 4 substituents (optionally 1 , 2 or 3) each independently selected from: halo, =0, -OR ^A , -NR ^A R ^B , -C(0)NR ^A R ^B , -C(0)R ^c , -CN, -NO2, C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, C1-4 alkyl substituted with -OR ^A , C3-6 heterocycloalkyl, C3-6 heterocycloalkyl substituted with -OR ^A , C1-4 alkyl substituted with phenyl, phenyl, -C(0)phenyl, -C(0)CH2phenyl, - C(0)Ophenyl, and -C(0)OCH ₂ phenyl. [0056] R may be substituted by 1 to 4 substituents (optionally 1 , 2 or 3) each independently selected from: halo, -OR ^A , -NR ^A R ^B , -C(0)NR ^A R ^B , -C(0)R ^c , -CN, -N0 ₂ , Ci- alkyl, Ci- haloalkyl, Ci- alkyl substituted with -OR ^A , Ci- ₄ alkyl substituted with phenyl, phenyl and -C(0)OCH2phenyl.

[0057] R may be substituted by 1 to 4 substituents (optionally 1 , 2 or 3) each independently selected from: halo, =0, -OR ^A , -NR ^A R ^B , -C(0)NR ^A R ^B , -C(0)R ^c , -CN, -N0 ₂ , Ci- alkyl, Ci- haloalkyl, C3-6 cycloalkyl, Ci- ₄ alkyl substituted with -OR ^A , Ci- ₄ alkyl substituted with phenyl, C3-6

heterocycloalkyl substituted with -OR ^A , phenyl and -C(0)OCH2phenyl.

[0058] R may be unsubstituted or substituted with 1 , 2 or 3 groups selected from: chloro, fluoro, bromo, methyl, ethyl, iso-propyl, tert-butyl, trifouromethyl, trifluoroethyl, -OH, -OMe, -OEt, -OCF3, - OCHF2, -NH2, -NHMe, -NMe ₂ , -NO2, -CN, -CH2OH , -CH2CH2OH, -C(0)Me, -C(0)NH ₂ , hydroxyethyl, hydroxypropyl, phenyl and -C(0)OCH2phenyl.

[0059] R may be unsubstituted or substituted with 1 , 2 or 3 groups selected from: chloro, fluoro, bromo, methyl, ethyl, iso-propyl, tert-butyl, difluoromethyl, triflouromethyl, trifluoroethyl, cyclopropyl; -OH, =0, -OMe, -OEt, -OCF3, -OCHF2, -NH ₂ , -NHMe, -NMe ₂ , -NO2, -CN, -CH2OH, -CH2CH2OH, - C(0)Me, -C(0)NH ₂ , -C(0)NHMe, -C(0)NMe ₂ , hydroxyethyl, hydroxypropyl, hydroxy-iso-propyl, methoxy-iso-propyl, hydroxyoxetane, phenyl and -C(0)OCH2phenyl.

[0060] R may be unsubstituted or substituted with a group or combination of groups selected from: fluoro; bromo; methyl; ethyl; iso-propyl; tert-butyl; trifouromethyl; trifluoroethyl; -OH; -OMe; - OEt; -OCF3; -OCHF2; -NH ₂ ; -NHMe; -NMe ₂ ; -NO2; -CN; -CH2OH ; -CH2CH2OH; -C(0)Me; -C(0)NH ₂ ; hydroxyethyl; hydroxypropyl; phenyl; -C(0)OCH2phenyl; dichloro; fluoro and methyl; fluoro and trifouromethyl; fluoro and methoxy; fluoro and bromo; chloro and trifouromethyl; fluoro and chloro; bromo and methoxy; methyl and methoxy; dimethoxy; methyl and isopropyl; -NMe∑ and

trifluoromethyl; -NMe∑ and methoxy; -C(0)NH2 and trifluoromethyl; difluoro and methoxy; and difluoro and chloro.

[0061] R may be unsubstituted or substituted with a group or combination of groups selected from: fluoro; bromo; methyl; ethyl; iso-propyl; tert-butyl; difluoromethyl; triflouromethyl; trifluoroethyl; cyclopropyl; -OH; =0, -OMe; -OEt; -OCF3; -OCHF2; -NH ₂ ; -NHMe; -NMe ₂ ; -NO2; -CN; -CH2OH ; - CH2CH2OH; -C(0)Me; -C(0)NH ₂ ; -C(0)NHMe; -C(0)NMe ₂ ; hydroxyethyl; hydroxypropyl; hydroxy- iso-propyl; methoxy-iso-propyl; hydroxyoxetane; phenyl; -C(0)OCH2phenyl; dichloro; fluoro and methyl; fluoro and trifouromethyl; fluoro and methoxy; fluoro and bromo; chloro and trifouromethyl; fluoro and chloro; bromo and methoxy; methyl and methoxy; dimethoxy; methyl and isopropyl; - ΝΜβ2 and trifluoromethyl; -NMe∑ and methoxy; -C(0)NH2 and trifluoromethyl; difluoro and methoxy; and difluoro and chloro.

[0062] R may be unsubstituted pyridyl, unsubstituted phenyl, unsubstituted pyridazinyl, methylphenyl, ethylphenyl, iso-propylphenyl, tert-butylphenyl, trifluoromethylphenyl, methoxyphenyl, ethyoxyphenyl, aminophenyl, N-methyl-aminophenyl, Ν,Ν-dimethyl-aminophenyl, nitrophenyl, cyanophenyl, methylpyridyl, ethylpyridyl, iso-propylpyridyl, tert-butylpyridyl, trifluoromethylpyridyl, methoxypyridyl, ethyoxypyridyl, aminopyridyl, N-methyl-aminopyridyl, N,N-dimethyl-aminopyridyl, nitropyridyl, cyanopyridyl, methylpyridazinyl, ethylpyridazinyl, iso-propylpyridazinyl, tert- butylpyridazinyl, trifluoromethylpyridazinyl, methoxypyridazinyl, ethyoxypyridazinyl,

aminopyridazinyl, N-methyl-aminopyridazinyl, Ν,Ν-dimethyl-aminopyridazinyl, nitropyridazinyl and cyanopyridazinyl.

[0063] In an embodiment there is provided compounds according to formula (Va) wherein R is selected from unsubstituted or substituted: phenyl, pyridyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, indanyl, indolyl, indolinyl, azaindolyl, benzthiazolyl, benzodioxolane, piperidinyl, piperazinyl, morpholinyl and pyrolidinyl

[0064] In an embodiment there is provided compounds according to formula (Vb) wherein R is selected from unsubstituted or substituted: phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazolyl, oxazolyl, thiazolyl, indolyl, indanyl, cyclohexyl and tetrahydropyranyl.

[0065] In an embodiment Z is Y ² .

[0066] In an embodiment the compound of formula (I) is a compound according to formula (VI):

(VI)

[0067] In an embodiment the two R ⁹ groups taken together form a heterocyclic ring system with the nitrogen atom to which they are attached, wherein the heterocyclic ring system is a 5 or 6 membered monocyclic ring system which is unsubstituted or substituted.

[0068] In an alternative embodiment the two R ⁹ groups taken together form a heterocyclic ring system with the nitrogen atom to which they are attached, wherein the heterocyclic ring system is a 8, 9, 10 or 1 1 membered bicyclic ring system which is unsubstituted or substituted.

[0069] In an embodiment the two R ⁹ groups taken together form a heterocyclic ring system with the nitrogen atom to which they are attached, wherein the heterocyclic ring system is selected from unsubstituted or substituted: pyrroline, pyrrolidine, pyrazoline, pyrazolidine, imidazoline, imidazolidine, piperidine, piperazine, pyrazole, imidazole, triazole, tetrazole, morpholine, thiomorpholine, pyridine, indoline, indole, isoindole, oxindole, isoxindole, indazole,

tetrahydroisoquinoline, tetrahydroquinoline, tetrahydroquinoxaline, dihydrobenzoxazole, dihydrobenzothiazine, benzotriazole tetrahydroquinolinone, dihydroisoquinolinone, pyrrolopyridine, benzomorpholine, purine, azaindole, and azaisoindole. [0070] Specifically, the two R ⁹ groups taken together form a heterocyclic ring system with the nitrogen atom to which they are attached, wherein the heterocyclic ring system is selected from unsubstituted or substituted: morpholine, thiomorpholine, pyridine, 1 ,2,3,4-tetrahydroisoquinoline, 1 ,2,3,4-tetrahydroquinoline, 1 ,2,3,4-tetrahydroquinoxaline, 2,3-dihydro-1 H-isoindole, 1 ,3-dihydro- 2,1 -benzoxazole, 2,3-dihydro-1 ,2-benzoxazole, indoline, indole, 3,4-dihydro-2H-1 ,4-benzothiazine, 1 ,2,3,4-tetrahydroquinolin-2-one, 1 ,2,3,4-tetrahydroisoquinolin-1 -one, 1 ,2-dihydroisoquinolin-1 -one, 2-pyrroline, pyrrolidine, 2-pyrazoline, pyrazolidine, 2-imidazoline, imidazolidine, piperidine, piperazine, pyrazole, imidazole, triazole, tetrazole, indazole, benzotriazole, 1 H-pyrrolo[2,3- b]pyridine, 1 H-pyrrolo[3,4-b]pyridine, 1 H-pyrrolo[3,2-b]pyridine, 1 H-pyrrolo[3,2-c]pyridine and 1 H- pyrrolo[2,3-c]pyridine.

[0071] Preferably, the two R ⁹ groups taken together form benzomorpholine.

[0072] In an embodiment R ² and R ³ are each independently selected from: H or methyl. In an embodiment, R ² and R ³ are H. In an alternative embodiment R ² and R ³ are methyl. In an alternative embodiment R ² is H and R ³ is methyl.

[0073] In an embodiment R ⁸ is selected from: H, methyl, ethyl, and trifluoromethyl. Preferably, R ⁸ may be H or methyl.

[0074] In an embodiment there are provide compounds of formulae (IV), (IVa), (IVb), (Va) or (Vb) or (VI) wherein: one of B , B ² , B ³ and B ⁴ is from C-OMe and the remaining B , B ² , B ³ and B ⁴ are CH; X is CR ⁰ R ¹¹ or O (preferably X is CH2 or O); and R ⁶ and R ⁷ are each independently selected from H or methyl (preferably H).

[0075] In an embodiment there are provided compounds of formulae (IV), (IVa), (IVb), (Va) or (Vb) or (VI) wherein: B\ B ² , B ³ and B ⁴ are CH; X is CR ⁰ R ¹¹ or O (preferably X is CH2 or O); and R ⁶ and R ⁷ are each independently selected from H or methyl (preferably H).

[0076] The compound according to the invention may be selected from a preferred group consisting of:







20

21

22











30

32

33





[0077] Where the above compounds have one or more chiral centres all enantiomers and diastereomers of the above compounds are contemplated by the invention. In one embodiment, compounds with one stereocentre have the (R)-configuration at the stereocentre. In an alternative embodiment compounds with one stereocentre have the (S)-configuration at the stereocentre. [0078] In accordance with another aspect, the present invention provides a compound of the present invention for use as a medicament.

[0079] In accordance with another aspect, the present invention provides a pharmaceutical formulation comprising a compound of the present invention and a pharmaceutically acceptable excipient.

[0080] In an embodiment the pharmaceutical composition may be a combination product comprising an additional pharmaceutically active agent. The additional pharmaceutically active agent may be an anti-tumor agent described below.

[0081] In accordance with another aspect, there is provided a compound of the present invention for use in the treatment of a condition which is modulated by Colony Stimulating Factor 1 Receptor (cFMS). Usually conditions that are modulated by cFMS are conditions that would be treated by the inhibition of cFMS, using a compound of the present invention. A compound of formula (I) may be for use in the treatment of a condition treatable by the inhibition of cFMS.

[0082] Modulation of cFMS is relevant for the treatment of many different diseases associated with the inhibition of cFMS. In embodiments the condition treatable by the inhibition of cFMS may be selected from: cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, leukemia, central nervous system disorders, inflammatory diseases, autoimmune diseases and immunological diseases. Specific cancers, sarcomas, melanomas, skin cancers, haematological tumors, lymphoma, carcinoma, leukemia, central nervous system disorders, inflammation and immunological diseases treatable by the inhibition of cFMS may be selected from: solid tumors; bone metastases; acute myeloid leukemia; tenosynovial giant cell tumour; breast cancer; metastatic breast cancer; metastatic melanoma; melanoma; gastrc cancer; refractory Hodgkin's lymphoma; glioblastoma; metastatic cancers; endometrial cancer; ovarian cancer; bone cancer; pancreatic cancer; myeloproliferative disorders such as polycythemia vera, essential thrombocytosis, primary or idiopathic myelofibrosis; systemic lupus erythematosus; acute disseminated encephalomyelitis; lupus nephtitis; arthritis; rheumatoid arthritis; cardiac hypertrophy; lung fibrosis; hepatic fibrosis; atherosclerosis; restenosis; glomerulonephritis; psoriasis; lupus; multiple sclerosis; macular degeneration; asthma; reactive synoviotides; reactive synoviotides such as pigmented villonodular synovitis; chronic infection; inflammatory bowel disease; sarcoidosis; immune-mediated nephritis; chronic obstrutive pulmonary disease and Sjogren's syndrome.

[0083] The invention contemplates methods of treating the above mentioned conditions and contemplates compounds of the invention for use in a method of treatment of the above mentioned conditions.

[0084] In an aspect of the invention, a compound of the invention may be for use in the treatment of a condition selected from: cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, leukemia, central nervous system disorders, neuro-degenerative disorders, inflammation and immunological diseases. Specific cancers, sarcomas, melanomas, skin cancers, haematological tumors, lymphoma, carcinoma, leukemia, central nervous system disorders, inflammation, autoimmune diseases and immunological diseases that may be treated by the compound of the invention may be selected from: solid tumors; bone metastases; acute myeloid leukemia; tenosynovial giant cell tumour; breast cancer; metastatic breast cancer; metastatic melanoma; melanoma; gastrc cancer; refractory Hodgkin lymphoma; Hodgkin lymphoma;

glioblastoma; metastatic cancers; endometrial cancer; ovarian cancer; bone cancer; pancreatic cancer; myeloproliferative disorders such as polycythemia vera, essential thrombocytosis, primary or idiopathic myelofibrosis; systemic lupus erythematosus; acute disseminated encephalomyelitis; lupus nephtitis; arthritis; rheumatoid arthritis; cardiac hypertrophy; lung fibrosis; hepatic fibrosis; atherosclerosis; restenosis; glomerulonephritis; psoriasis; lupus; multiple sclerosis; macular degeneration; asthma; reactive synoviotides; reactive synoviotides such as pigmented villonodular synovitis; chronic infection; a inflammatory bowel disease; sarcoidosis; immune-mediated nephritis; chronic obstrutive pulmonary disease and Sjogren's syndrome.

[0085] In an aspect of the invention there is provided a method of treatment of a condition which is modulated by cFMS, wherein the method comprises administering a therapeutic amount of a compound of the invention, to a patient in need thereof.

[0086] The method of treatment may be a method of treating a condition treatable by the inhibition of cFMS. These conditions are described above in relation to conditions treatable by the inhibition of cFMS.

[0087] In an aspect of the invention there is provided a method of treatment of a condition selected from: cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, leukemia, central nervous system disorders, neuro-degenerative disorders, inflammation and immunological diseases wherein the method comprises administering a therapeutic amount of a compound of the invention, to a patient in need thereof. Specific cancers, sarcomas, melanomas, skin cancers, haematological tumors, lymphoma, carcinoma, leukemia, central nervous system disorders, inflammation, autoimmune diseases and immunological diseases that may be treated by the method of treatment may be selected from: solid tumors; bone metastases; acute myeloid leukemia; tenosynovial giant cell tumour; breast cancer; metastatic breast cancer; metastatic melanoma; melanoma; gastrc cancer; refractory Hodgkin's lymphoma; glioblastoma; metastatic cancers; endometrial cancer; ovarian cancer; bone cancer; pancreatic cancer; myeloproliferative disorders such as polycythemia vera, essential thrombocytosis, primary or idiopathic myelofibrosis; systemic lupus erythematosus; acute disseminated encephalomyelitis; lupus nephtitis; arthritis; rheumatoid arthritis; cardiac hypertrophy; lung fibrosis; hepatic fibrosis; atherosclerosis; restenosis; glomerulonephritis; psoriasis; lupus; multiple sclerosis; macular degeneration; asthma; reactive synoviotides; reactive synoviotides such as pigmented villonodular synovitis; chronic infection; inflammatory bowel disease; sarcoidosis; immune-mediated nephritis; chronic obstrutive pulmonary disease and Sjogren's syndrome.

[0088] In an aspect of the invention there is provided a use of a compound of the invention in the manufacture of a medicament for the treatment of a condition which is modulated by cFMS. Usually conditions that are modulated by cFMS are conditions that would be treated by the inhibition of cFMS, using a compound of the present invention. In an embodiment there is provided a use of a compound of the invention in the manufacture of a medicament for the treatment of a condition treatable by the inhibition of cFMS. The condition may be any of the conditions mentioned above.

[0089] In accordance with another aspect, the present invention provides methods of treating a medical condition that benefits from the inhibition of cFMS comprising administering an effective amount of a compound according to the present invention.

[0090] In accordance with another aspect, the present invention provides methods of enhancing the effectiveness of an anti-cancer treatment comprising administering an anti-cancer agent and a compound according to the present invention.

[0091] In an aspect of the invention there is provided a compound for use in a method of treating a condition that benefits from the inhibition and/or reduction of tumor associated macrophage.

[0092] In an aspect of the invention there is provided a method of treating a condition that benefits from the inhibition and/or reduction of tumor associated macrophage, wherein the method comprises administering a compound of the invention.

[0093] In an aspect of the invention there is provided a compound for use in a method of treating a condition that benefits from inhibition of osteoclast formation.

[0094] In an aspect of the invention there is provided a method of treating a condition that benefits from inhibition of osteoclast formation, wherein the method comprises administering a compound of the invention.

[0095] In an aspect of the invention there is provided a method of inhibiting osteoclast formation, wherein the method comprises administering a compound of the invention.

[0096] In an aspect of the invention there is provided a method of preventing bone and joint damage associated with osteoclast formation, wherein the method comprises administering a therapeutic amount of the compound of the invention.

[0097] In accordance with another aspect, the present invention provides a compound of the present invention for use in treating cFMS mediated immunosuppression.

[0098] In accordance with another aspect, the present invention provides a compound of the present invention for use in treating immunosuppression.

[0099] In accordance with another aspect, the present invention provides a compound of the present invention for use in treating immunosuppression associated with cancer, in particular for use in treating tumour-specific immunosuppression associated with cancer.

[00100] Cancer may refer to any one or more of: solid tumors; bone metastases acute myeloid leukemia; tenosynovial giant cell tumour; breast cancer; metastatic breast cancer; metastatic melanoma; melanoma; gastrc cancer; refractory Hodgkin's lymphoma; glioblastoma; metastatic cancers; cervical cancer; endometrial cancer; ovarian cancer; bone cancer and pancreatic cancer.

[00101] Inflammatory diseases, autoimmune diseases and immunological diseases, as appropriate, may refer to any one or more of: myeloproliferative disorders such as polycythemia vera, essential thrombocytosis, primary or idiopathic myelofibrosis; systemic lupus erythematosus; acute disseminated encephalomyelitis; lupus nephtitis; arthritis; rheumatoid arthritis; cardiac hypertrophy; lung fibrosis; hepatic fibrosis; atherosclerosis; restenosis; glomerulonephritis;

psoriasis; lupus; multiple sclerosis; macular degeneration; asthma; reactive synoviotides; reactive synoviotides such as pigmented villonodular synovitis; chronic infection; inflammatory bowel disease; sarcoidosis; immune-mediated nephritis; chronic obstrutive pulmonary disease and Sjogren's syndrome.

DETAILED DESCRIPTION

[00102] Given below are definitions of terms used in this application. Any term not defined herein takes the normal meaning as the skilled person would understand the term.

[00103] The term "halo" refers to one of the halogens, group 17 of the periodic table. In particular the term refers to fluorine, chlorine, bromine and iodine. Preferably, the term refers to fluorine or chlorine.

[00104] The term "Ci-e alkyl" refers to a linear or branched hydrocarbon chain containing 1 , 2, 3, 4, 5 or 6 carbon atoms, for example methyl, ethyl, n-propyl, / ^' so-propyl, n-butyl, sec-butyl, fe/ -butyl, n- pentyl and n-hexyl. Alkylene groups may likewise be linear or branched and may have two places of attachment to the remainder of the molecule. Furthermore, an alkylene group may, for example, correspond to one of those alkyl groups listed in this paragraph. The alkyl and alkylene groups may be unsubstituted or substituted by one or more substituents. Possible substituents are described below. Substituents for the alkyl group may be halogen, e.g. fluorine, chlorine, bromine and iodine, OH, Ci-e alkoxy.

[00105] The term "Ci-e alkoxy" refers to an alkyl group which is attached to a molecule via oxygen. This includes moieties where the alkyl part may be linear or branched and may contain 1 , 2, 3, 4, 5 or 6 carbon atoms, for example methyl, ethyl, n-propyl, / ^' so-propyl, n-butyl, sec-butyl, fe/ -butyl, n- pentyl and n-hexyl. Therefore, the alkoxy group may be methoxy, ethoxy, n-propoxy, / ^' so-propoxy, n- butoxy, sec-butoxy, fe/f-butoxy, π-pentoxy and π-hexoxy. The alkyl part of the alkoxy group may be unsubstituted or substituted by one or more substituents. Possible substituents are described below. Substituents for the alkyl group may be halogen, e.g. fluorine, chlorine, bromine and iodine, OH, Ci-e alkoxy.

[00106] The term "Ci-e haloalkyl" refers to a hydrocarbon chain substituted with at least one halogen atom independently chosen at each occurrence, for example fluorine, chlorine, bromine and iodine. The halogen atom may be present at any position on the hydrocarbon chain. For example, Ci-e haloalkyl may refer to chloromethyl, flouromethyl, trifluoromethyl, chloroethyl e.g. 1 - chloromethyl and 2-chloroethyl, trichloroethyl e.g. 1 ,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl e.g. 1 -fluoromethyl and 2-fluoroethyl, trifluoroethyl e.g. 1 ,2,2-trifluoroethyl and 2,2,2- trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl.

[00107] The term "C2-6 alkenyl" refers to a branched or linear hydrocarbon chain containing at least one double bond and having 2, 3, 4, 5 or 6 carbon atoms. The double bond(s) may be present as the E or Z isomer. The double bond may be at any possible position of the hydrocarbon chain. For example, the "C2-6 alkenyl" may be ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl.

[00108] The term "C2-6 alkynyl" refers to a branched or linear hydrocarbon chain containing at least one triple bond and having 2, 3, 4, 5 or 6 carbon atoms. The triple bond may be at any possible position of the hydrocarbon chain. For example, the "C2-6 alkynyl" may be ethynyl, propynyl, butynyl, pentynyl and hexynyl.

[00109] The term "C1-6 heteroalkyl" refers to a branched or linear hydrocarbon chain containing 1 , 2, 3, 4, 5, or 6 carbon atoms and at least one heteroatom selected from N, O and S positioned between any carbon in the chain or at an end of the chain. For example, the hydrocarbon chain may contain one or two heteroatoms. The C1-6 heteroalkyl may be bonded to the rest of the molecule through a carbon or a heteroatom. For example, the "C1-6 heteroalkyl" may be C1-6 /V-alkyl, C1-6 Λ ,/V-alkyl, or C1-6 O-alkyl.

[001 10] The term "carbocyclic" refers to a saturated or unsaturated carbon containing ring system. A "carbocyclic" system may be monocyclic or a fused polycyclic ring system, for example, bicyclic or tricyclic. A "carbocyclic" moiety may contain from 3 to 14 carbon atoms, for example, 5 to 10 carbon atoms in a monocyclic system ai- --7 -to -44 ~&a¥bo& -atoms -mor a polycyclic system. "Carbocyclic" encompasses cycloalkyl moieties, cycloalkenyl moieties, aryl ring systems and fused ring systems including an aromatic portion.

[001 11] The term "heterocyclic" refers to a saturated or unsaturated ring system containing at least one heteroatom selected from N, O or S. A "heterocyclic" system may contain 1 , 2, 3 or 4 heteroatoms, for example 1 or 2. A "heterocyclic" system may be monocyclic or a fused polycyclic ring system, for example, bicyclic or tricyclic. A "heterocyclic" moiety may contain from 3 to 14 carbon atoms, for example, 5 to 10 carbon atoms in a monocyclic system

iff or a polycyclic system. "Heterocyclic" encompasses heterocycloalkyl moieties, heterocycloalkenyl moieties and heteroaromatic moieties. For example, the heterocyclic group may be: oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, tetrahydropyran, pyrroline, pyrazoline, imidazoline, pyrazole, imidazole, triazole, tetrazole, pyridine, indoline, indole, isoindole, oxindole, isoxindole, indazole, tetrahydroisoquinoline, tetrahydroquinoline, tetrahydroquinoxaline, dihydrobenzoxazole, dihydrobenzothiazine,

benzotriazole tetrahydroquinolinone, dihydroisoquinolinone, pyrrolopyridine, benzomorpholine, purine, azaindole, and azaisoindole.

[001 12] The term "cycloalkyl" refers to a saturated hydrocarbon ring system. The "cycloalkyl" group may be denoted as a "C3-10 cycloalkyl" containing 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The ring system may be a single ring or a bi-cyclic or tri-cyclic ring system. The term "cycloalkyl" may also refer to "C3-8 cycloalkyl" refering to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms. For example, the "C3-8 cycloalkyl" may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. [00113] The term "cycloalkenyl" refers to an unsaturated hydrocarbon ring system that is not aromatic. The "cycloalkenyl" group may be denoted as a "C3-10 cycloalkenyl". A "C3-10 cycloalkenyl" is a ring system containing 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The term"cycloalkenyl" may also refer to "C3-8 cycloalkenyl" refering to an unsaturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms that is not aromatic. The ring may contain more than one double bond provided that the ring system is not aromatic. The ring system may be a single ring or a bi-cyclic or tri-cyclic ring system. For example, the "C3-8 cycloalkyl" may be cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienly, cycloheptenyl, cycloheptadiene, cyclooctenyl and cyclooctadienyl.

[00114] The term "heterocycloalkyl" refers to a saturated hydrocarbon ring system with at least one heteroatom within the ring selected from N, O and S. The "heterocycloalkyl" group may be denoted as a "C5-10 heterocycloalkyl". A "C5-10 heterocycloalkyl" is a ring system containing 5, 6, 7, 8, 9 or 10 atoms at least one being a heteroatom selected from N, O and S. For example there may be 1 , 2 or 3 heteroatoms, optionally 1 or 2. The "heterocycloalkyl" group may also be denoted as a "3 to 10 membered heterocycloalkyl" which is also a ring system containing 3, 4, 5, 6, 7, 8, 9 or 10 atoms at least one being a heteroatom. The ring system may be a single ring or a bi-cyclic or tricyclic ring system. Where the ring system is bicyclic one of the rings may be an aromatic ring, for example as in indane. The "heterocycloalkyl" may be bonded to the rest of the molecule through any carbon atom or heteroatom. The "C5-10 heterocycloalkyl" may have one or more, e.g. one or two, bonds to the rest of the molecule: these bonds may be through any of the atoms in the ring. For example, the "C5-10 heterocycloalkyl" may be oxirane, aziridine, azetidine, oxetane,

tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and

tetrahydropyran.

[00115] The term "heterocycloalkenyl" refers to an unsaturated hydrocarbon ring system that is not aromatic, having at least one heteroatom within the ring selected from N, O and S. The

"heterocycloalkenyl" group may be denoted as a "C5-10 heterocycloalkenyl". A "C5-10

heterocycloalkenyl" is a ring system containing 5, 6, 7, 8, 9 or 10 atoms at least one being a heteroatom selected from N, O and S. For example there may be 1 , 2 or 3 heteroatoms, optionally 1 or 2. The "heterocycloalkenyl" group may also be denoted as a "3 to 10 membered

heterocycloalkenyl" which is also a ring system containing 3, 4, 5, 6, 7, 8, 9 or 10 atoms at least one being a heteroatom. The ring system may be a single ring or a bi-cyclic or tri-cyclic ring system. Where the ring system is bicyclic one of the rings may be an aromatic ring, for example as in indoline and dihydrobenzofuran. The "heterocycloalkenyl" may be bonded to the rest of the molecule through any carbon atom or heteroatom. The "heterocycloalkenyl" may have one or more, e.g. one or two, bonds to the rest of the molecule: these bonds may be through any of the atoms in the ring. The "C5-10 heterocycloalkenyl" may be bonded to the rest of the molecule through any carbon atom or heteroatom. The "C5-10 heterocycloalkenyl" may have one or more, e.g. one or two, bonds to the rest of the molecule: these bonds may be through any of the atoms in the ring. For example, the "C5-10 heterocycloalkyl" may be tetrahydropyridine, dihydropyran, dihydrofuran, pyrroline.

[00116] The term "aromatic" when applied to a substituent as a whole means a single ring or polycyclic ring system with 4n + 2 electrons in a conjugated π system within the ring or ring system where all atoms contributing to the conjugated π system are in the same plane.

[00117] The term "aryl" refers to an aromatic hydrocarbon ring system. The ring system has 4n +2 electrons in a conjugated π system within a ring where all atoms contributing to the conjugated π system are in the same plane. For example, the "aryl" may be phenyl and naphthyl. The aryl system itself may be substituted with other groups.

[00118] The term "heteroaryl" refers to an aromatic hydrocarbon ring system with at least one heteroatom within a single ring or within a fused ring system, selected from O, N and S. The ring or ring system has 4n +2 electrons in a conjugated π system where all atoms contributing to the conjugated π system are in the same plane. For example, the "heteroaryl" may be imidazole, thiene, furane, thianthrene, pyrrol, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine and indole.

[00119] The term "alkaryl" refers to an aryl group, as defined above, bonded to a C1-4 alkyl, where the C1-4 alkyl group provides attachment to the remainder of the molecule.

[00120] The term "alkheteroaryl" refers to a heteroaryl group, as defined above, bonded to a C1-4 alkyl, where the alkyl group provides attachment to the remainder of the molecule.

[00121] The term "halogen" herein includes reference to F, CI, Br and I. Halogen may be CI. Halogen may be F.

[00122] A bond terminating in a " - ^r/ ~ ^r " represents that the bond is connected to another atom that is not shown in the structure. A bond terminating inside a cyclic structure and not terminating at an atom of the ring structure represents that the bond may be connected to any of the atoms in the ring structure where allowed by valency.

[00123] Where a moiety is substituted, it may be substituted at any point on the moiety where chemically possible and consistent with atomic valency requirements. The moiety may be substituted by one or more substituents, e.g. 1 , 2, 3 or 4 substituents; optionally there are 1 or 2 substituents on a group. Where there are two or more substituents, the substituents may be the same or different. The substituent(s) may be selected from: OH, NHR, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, C(0)H, acyl, acyloxy, carboxy, sulfo, sulfamoyl, carbamoyl, cyano, azo, nitro, halo, C1-3 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl or alkaryl. Where the group to be substituted is an alkyl group the substituent may be =0. R may be selected from H, C1-6 alkyl, C3-8 cycloalkyl, phenyl, benzyl or phenethyl group, e.g. R is H or C1-3 alkyl. Where the moiety is substituted with two or more substituents and two of the substituents are adjacent the adjacent substituents may form a C4-8 ring along with the atoms of the moiety on which the substituents are substituted, wherein the C4-8 ring is a saturated or unsaturated hydrocarbon ring with 4, 5, 6, 7, or 8 carbon atoms or a saturated or unsaturated hydrocarbon ring with 4, 5, 6, 7, or 8 carbon atoms and 1 , 2 or 3 heteroatoms.

[00124] Substituents are only present at positions where they are chemically possible, the person skilled in the art being able to decide (either experimentally or theoretically) without inappropriate effort which substitutions are chemically possible and which are not.

[00125] Ortho, meta and para substitution are well understood terms in the art. For the absence of doubt, "ortho" substitution is a substitution pattern where adjacent carbons possess a substituent, whether a simple group, for example the fluoro group in the example below, or other portions of the molecule, as indicated by the bond ending in " - ^r/ ~ ^r ".

[00126] "Meta" substitution is a substitution pattern where two substituents are on carbons one carbon removed from each other, i.e with a single carbon atom between the substituted carbons. In other words there is a substituent on the second atom away from the atom with another substituent. For example the groups below are meta substituted.

[00127] "Para" substitution is a substitution pattern where two substituents are on carbons two carbons removed from each other, i.e with two carbon atoms between the substituted carbons. In other words there is a substituent on the third atom away from the atom with another substituent. For example the groups below are para substituted.

[00128] By "acyl" is meant an organic radical derived from, for example, an organic acid by the removal of the hydroxyl group, e.g. a radical having the formula R-C(O)-, where R may be selected from H, Ci-6 alkyl, C3-8 cycloalkyl, phenyl, benzyl or phenethyl group, eg R is H or C1-3 alkyl. In one embodiment acyl is alkyl-carbonyl. Examples of acyl groups include, but are not limited to, formyl, acetyl, propionyl and butyryl. A particular acyl group is acetyl.

[00129] Throughout the description the disclosure of a compound also encompasses

pharmaceutically acceptable salts, solvates and stereoisomers thereof. Where a compound has a stereocentre, both (R) and (S) stereoisomers are contemplated by the invention, equally mixtures of stereoisomers or a racemic mixture are completed by the present application. Where a compound of the invention has two or more stereocentres any combination of (R) and (S) stereoisomers is contemplated . The combination of (R) and (S) stereoisomers may result in a diastereomeric mixture or a single diastereoisomer. The compounds of the invention may be present as a single stereoisomer or may be mixtures of stereoisomers, for example racemic mixtures and other enantiomeric mixtures, and diasteroemeric mixtures. Where the mixture is a mixture of enantiomers the enantiomeric excess may be any of those disclosed above. Where the compound is a single stereoisomer the compounds may still contain other diasteroisomers or enantiomers as impurities. Hence a single stereoisomer does not necessarily have an enantiomeric excess (e.e.) or diastereomeric excess (d.e.) of 100% but could have an e.e. or d.e. of about at least 85%

[00130] The invention contemplates pharmaceutically acceptable salts of the compounds of the invention . These may include the acid addition and base salts of the compounds. These may be acid addition and base salts of the compounds. In addition the invention contemplates solvates of the compounds. These may be hydrates or other solvated forms of the compound.

[00131] Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 1 ,5- naphthalenedisulfonate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts.

[00132] Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts. For a review on suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection , and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[00133] Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by one or more of three methods:

[00134] by reacting the compound of the invention with the desired acid or base;

[00135] by removing an acid- or base-labile protecting group from a suitable precursor of the compound of the invention or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or

[00136] by converting one salt of the compound of the invention to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.

[00137] All three reactions are typically carried out in solution . The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised. [00138] The compounds of the invention may exist in both unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water.

[00139] Included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non- stoichiometric amounts. The resulting complexes may be ionised, partially ionised, or non- ionised. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975).

[00140] Hereinafter all references to compounds of any formula include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.

[00141] The compounds of the invention include compounds of a number of formula as herein defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labelled compounds of the invention.

[00142] The present invention also includes all pharmaceutically acceptable isotopically-labelled compounds of the invention wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.

[00143] Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as ² H and ³ H, carbon, such as C, ³ C and ⁴ C, chlorine, such as ³⁶ CI, fluorine, such as ⁸ F, iodine, such as ²³ l and ²⁵ l, nitrogen, such as ³ N and ⁵ N, oxygen, such as 50, ⁷ 0 and ⁸ 0, phosphorus, such as ³² P, and sulphur, such as ³⁵ S.

[00144] Certain isotopically-labelled compounds, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. ³ H, and carbon-14, i.e. ⁴ C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

[00145] Substitution with heavier isotopes such as deuterium, i.e. ² H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

[00146] Before purification, the compounds of the present invention may exist as a mixture of enantiomers depending on the synthetic procedure used. The enantiomers can be separated by conventional techniques known in the art. Thus the invention covers individual enantiomers as well as mixtures thereof.

[00147] For some of the steps of the process of preparation of the compounds of the invention, it may be necessary to protect potential reactive functions that are not wished to react, and to cleave said protecting groups in consequence. In such a case, any compatible protecting radical can be used. In particular methods of protection and deprotection such as those described by T.W.

GREENE (Protective Groups in Organic Synthesis, A. Wiley- Interscience Publication, 1981) or by P. J. Kocienski (Protecting groups, Georg Thieme Verlag, 1994), can be used. All of the above reactions and the preparations of novel starting materials used in the preceding methods are conventional and appropriate reagents and reaction conditions for their performance or preparation as well as procedures for isolating the desired products will be well-known to those skilled in the art with reference to literature precedents and the examples and preparations hereto.

[00148] Also, the compounds of the present invention as well as intermediates for the preparation thereof can be purified according to various well-known methods, such as for example

crystallization or chromatography.

[00149] One or more compounds of the invention may be combined with one or more

pharmaceutical agents, for example anti-viral agents, chemotherapeutics, anti cancer agents, immune enhancers, immunosuppressants, anti-tumour vaccines, anti-viral vaccines, cytokine therapy, or tyrosine kinase inhibitors, for the treatment of conditions modulated by the inhibition of cFMS, for example cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, leukemia, central nervous system disorders, inflammation and immunological diseases

[00150] The method of treatment or the compound for use in the treatment of cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, leukemia, central nervous system disorders, inflammation and immunological diseases as defined hereinbefore may be applied as a sole therapy or be a combination therapy with an additional active agent.

[00151] The method of treatment or the compound for use in the treatment of cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, leukemia, and central nervous system disorders may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumor agents:

[00152] (i) antiproliferative/antineoplastic drugs and combinations thereof, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, uracil mustard, bendamustin, melphalan, chlorambucil, chlormethine, busulphan, temozolamide, nitrosoureas, ifosamide, melphalan, pipobroman, triethylene-melamine, triethylenethiophoporamine, carmustine, lomustine, stroptozocin, temozolomide and dacarbazine); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, pemetrexed, cytosine arabinoside, floxuridine, cytarabine, 6-mercaptopurine, 6- thioguanine, fludarabine phosphate, pentostatine, and gemcitabine and hydroxyurea); antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere and polokinase inhibitors and eribulin); proteasome inhibitors, for example carfilzomib and bortezomib; interferon therapy; and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan, mitoxantrone and camptothecin); bleomcin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (Taxol™), nabpaclitaxel, docetaxel, mithramycin, deoxyco-formycin, mitomycin-C, L-asparaginase, interferons (especially IFN-a), etoposide, and teniposide;

[00153] (ii) cytostatic agents such as antiestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a- reductase such as finasteride; and navelbene, CPT-II, anastrazole, letrazole, capecitabine, reloxafme, cyclophosphamide, ifosamide, and droloxafine;

[00154] (iii) anti-invasion agents, for example dasatinib and bosutinib (SKI-606), and metalloproteinase inhibitors, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase;

[00155] (iv) inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies, for example the anti-erbB2 antibody trastuzumab [Herceptin™], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab, tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as gefitinib, erlotinib, 6-acrylamido-/V-(3-chloro-4- fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib) and antibodies to costimulatory molecules such as CTLA-4, 4-IBB and PD-I, or antibodies to cytokines (IL-I0, TGF-beta); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; modulators of protein regulators of cell apoptosis (for example Bcl-2 inhibitors); inhibitors of the platelet-derived growth factor family such as imatinib and/or nilotinib (AMN107); inhibitors of serine/threonine kinases (for example Ras/Raf signalling inhibitors such as farnesyl transferase inhibitors, for example sorafenib , tipifarnib and lonafarnib), inhibitors of cell signalling through MEK and/or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1 R kinase inhibitors, IGF receptor, kinase inhibitors; aurora kinase inhibitors and cyclin dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors; and CCR2, CCR4 or CCR6 modulator;

[00156] (v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (Avastin™); thalidomide; lenalidomide; and for example, a VEGF receptor tyrosine kinase inhibitor such as vandetanib, vatalanib, sunitinib, axitinib and pazopanib;

[00157] (vi) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2;

[00158] (vii) immunotherapy approaches, including for example antibody therapy such as alemtuzumab, rituximab, ibritumomab tiuxetan (Zevalin®) and ofatumumab; interferons such as interferon a; interleukins such as IL-2 (aldesleukin); interleukin inhibitors for example IRAK4 inhibitors; cancer vaccines including prophylactic and treatment vaccines such as HPV vaccines, for example Gardasil, Cervarix, Oncophage and Sipuleucel-T (Provenge); gp100;dendritic cell-based vaccines (such as Ad.p53 DC); and toll-like receptor modulators for example TLR-7 or TLR-9 agonists; and

[00159] (viii) cytotoxic agents for example fludaribine (fludara), cladribine, pentostatin (Nipent™);

[00160] (ix) steroids such as corticosteroids, including glucocorticoids and mineralocorticoids, for example aclometasone, aclometasone dipropionate, aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol propionate, cloprednol, cortisone, cortisone acetate, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, difluorocortolone, fluclorolone, flumethasone, flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluorocortisone, fluorocortolone, fluocortolone caproate, fluocortolone pivalate, fluorometholone, fluprednidene, fluprednidene acetate, flurandrenolone, fluticasone, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone valerate, icomethasone, icomethasone enbutate, meprednisone, methylprednisolone, mometasone paramethasone, mometasone furoate monohydrate, prednicarbate, prednisolone, prednisone, tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide, triamcinolone alcohol and their respective pharmaceutically acceptable derivatives. A combination of steroids may be used, for example a combination of two or more steroids mentioned in this paragraph;

[00161] (x) targeted therapies, for example PI3Kd inhibitors, for example idelalisib and perifosine; PD-1 , PD-L1 , PD-L2 and CTL4-A modulators, antibodies and vaccines; IDO inhibitors (such as indoximod); Raf enzyme inhibitors for example vemurafenib; anti-PD-1 monoclonal antibodies (such as MK-3475 and nivolumab); anti-PDL1 monoclonal antibodies (such as MEDI- 4736 and RG-7446); anti-PDL2 monoclonal antibodies; and anti-CTLA-4 antibodies (such as ipilimumab);

[00162] (xi) anti-viral agents such as nucleotide reverse transcriptase inhibitors (for example, zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, adefovir diprovoxil, lobucavir, BCH-10652, emitricitabine, beta-L-FD4 (also called 3'-dicleoxy-5-fluoro-cytidine), (-)-beta-D-2,6- diamino-purine dioxolane, and lodenasine), non-nucleoside reverse transcriptase inhibitors (for example, nevirapine, delaviradine, efavirenz, PNU-142721 , AG-1549, MKC-442 (1 -ethoxy-methyl)- 5-(1 -methylethyl)-6-(phenylmehtyl)-(2,4(1 H,3H)pyrimidineone), and (+)-alanolide A and B) and protease inhibitors (for example, saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lasinavir, DMP-450, BMS-2322623, ABT-378 and AG-1 549);

[00163] (xii) chimeric antigen receptors, anticancer vaccines and arginase inhibitors.

[00164] The method of treatment or the compound for use in the treatment of inflammation and immunological diseases may involve, in addition to the compound of the invention, additional active agents. The additional active agents may be one or more active agents used to treat the condition being treated by the compound of the invention and additional active agent. The additional active agents may include one or more of the following active agents:-

[00165] (i) steroids such as corticosteroids, including glucocorticoids and mineralocorticoids, for example aclometasone, aclometasone dipropionate, aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol propionate, cloprednol, cortisone, cortisone acetate, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, difluorocortolone, fluclorolone, flumethasone, flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluorocortisone, fluorocortolone, fluocortolone caproate, fluocortolone pivalate, fluorometholone, fluprednidene, fluprednidene acetate, flurandrenolone, fluticasone, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone valerate, icomethasone, icomethasone enbutate, meprednisone, methylprednisolone, mometasone paramethasone, mometasone furoate monohydrate, prednicarbate, prednisolone, prednisone, tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide, triamcinolone alcohol and their respective pharmaceutically acceptable derivatives. A combination of steroids may be used, for example a combination of two or more steroids mentioned in this paragraph;

[00166] (ii) TNF inhibitors for example etanercept; monoclonal antibodies (e.g. infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi)); fusion proteins (e.g. etanercept (Enbrel)); and 5-ΗΪ2Α agonists (e.g. 2,5-dimethoxy-4-iodoamphetamine, TCB-2, lysergic acid diethylamide (LSD), lysergic acid dimethylazetidide);

[00167] (iii) anti-inflammatory drugs, for example non-steroidal anti-inflammatory drugs;

[00168] (iv) dihydrofolate reductase inhibitors/antifolates, for example methotrexate, trimethoprim, brodimoprim, tetroxoprim, iclaprim, pemetrexed, ralitrexed and pralatrexate; and

[00169] (v) immunosuppressants for example cyclosporins, tacrolimus, sirolimus pimecrolimus, angiotensin II inhibitors (e.g. Valsartan, Telmisartan, Losartan, Irbesatan, Azilsartan, Olmesartan, Candesartan, Eprosartan) and ACE inhibitors e.g. sulfhydryl-containing agents (e.g. Captopril, Zofenopril), dicarboxylate-containing agents (e.g. Enalapril, Ramipril, Quinapril, Perindopril, Lisinopril, Benazepril, Imidapril, Zofenopril, Trandolapril), phosphate-containing agents (e.g.

Fosinopril), casokinins, lactokinins and lactotripeptides.

[00170] Such combination treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention within a therapeutically effective dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.

[00171] Compounds of the invention may exist in a single crystal form or in a mixture of crystal forms or they may be amorphous. Thus, compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, or spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.

[00172] For the above-mentioned compounds of the invention the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. For example, if the compound of the invention is administered orally, then the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight ^g/kg) to 100 milligrams per kilogram body weight (mg/kg).

[00173] A compound of the invention, or pharmaceutically acceptable salt thereof, may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the compounds of the invention, or pharmaceutically acceptable salt thereof, is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example,

"Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.

[00174] Depending on the mode of administration of the compounds of the invention, the pharmaceutical composition which is used to administer the compounds of the invention will preferably comprise from 0.05 to 99 %w (per cent by weight) compounds of the invention, more preferably from 0.05 to 80 %w compounds of the invention, still more preferably from 0.10 to 70 %w compounds of the invention, and even more preferably from 0.10 to 50 %w compounds of the invention, all percentages by weight being based on total composition.

[00175] The pharmaceutical compositions may be administered topically (e.g. to the skin) in the form, e.g., of creams, gels, lotions, solutions, suspensions, or systemically, e.g. by oral

administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of a sterile solution, suspension or emulsion for injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion); by rectal administration in the form of suppositories; or by inhalation in the form of an aerosol.

[00176] For oral administration the compounds of the invention may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.

Alternatively, the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.

[00177] For the preparation of soft gelatine capsules, the compounds of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets. Also liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules. Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, sweetening agents (such as saccharine), preservative agents and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.

[00178] For intravenous (parenteral) administration the compounds of the invention may be administered as a sterile aqueous or oily solution.

[00179] The size of the dose for therapeutic purposes of compounds of the invention will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.

[00180] Dosage levels, dose frequency, and treatment durations of compounds of the invention are expected to differ depending on the formulation and clinical indication, age, and co-morbid medical conditions of the patient. The standard duration of treatment with compounds of the invention is expected to vary between one and seven days for most clinical indications. It may be necessary to extend the duration of treatment beyond seven days in instances of recurrent infections or infections associated with tissues or implanted materials to which there is poor blood supply including bones/joints, respiratory tract, endocardium, and dental tissues.

EXAMPLES AND SYNTHESIS

[00181] As used herein the following terms have the meanings given: "BuLi" refers to n- butyllithium; "fBuXPhos" refers to 2-di-fe/ -butylphosphino-2',4',6'-triisopropylbiphenyl; "fBuXPhos Pd G1 " refers to chloro[2-(di-te/ -butylphosphino)-2',4',6'-triisopropyl-1 ,1 '-biphenyl][2-(2- aminoethyl)phenyl)]palladium(ll); "Cbz" refers to carboxybenzyl; "CBzOSu" refers to N- (benzyloxycarbonyloxy) succinimide; "DCM" refers to dichloromethane; "DEAD" refers to diethyl azodicarboxylate; "DIAD" refers to diisopropyl azodicarboxylate; "DMF" refers to N,N- dimethylformamide; "EDC" refers to /V-(3-Dimethylaminopropyl)-/V'-ethylcarbodiimide; "HBTU" refers to (1 H-Benzotriazol-1 -yloxy)(dimethylamino)-/V,/V-dimethylmethaniminium hexafluorophosphate; "LCMS" refers to liquid chromatography/mass spectrometry; "min" refers to minutes; "rt" refers to retention time; "SCX" refers to strong cation exchange; "STAB" refers to sodium

triacetoxyborohydride; "T3P" refers to propylphosphonic anhydride; "TBAF" refers to

tetrabutylammonium fluoride, "TFA" refers to trifluoroacetic acid and "THF" refers to tetrahydrofuran.

[00182] Solvents, reagents and starting materials were purchased from commercial vendors and used as received unless otherwise described. All reactions were performed at room temperature unless otherwise stated. Compound identity and purity confirmations were performed by LCMS UV using a Waters Acquity SQ Detector 2 (ACQ-SQD2#LCA081). The diode array detector wavelength was 254nM and the MS was in positive and negative electrospray mode (m/z: 150-800). A 2\\L aliquot was injected onto a guard column (0.2μηι x 2 mm filters) and UPLC column (C18, 50 x 2.1 mm, < 2μηι) in sequence maintained at 40 °C. The samples were eluted at a flow rate of 0.6mL/min with a mobile phase system composed of A (0.1 % (v/v) Formic Acid in Water) and B (0.1 % (v/v) Formic Acid in Acetonitrile) according to the gradients outlined in Table 1 below. Retention times RT are reported in minutes.

Table 1

[00183] Compound identity confirmations were also performed by LCMS UV using a Waters Alliance 2695 micromass ZQ (K98SM4 512M-LAA434). The diode array detector wavelength was 254nM and the MS was in positive and negative electrospray mode (m/z: 150-650). A 10μΙ_ aliquot was injected onto an HPLC column (C18, 75 x 4.6 mm, 2.5μηι) at room temperature which was controlled at 19 °C. The samples were eluted at a flow rate of 0.9ml_/min with a mobile phase system composed of A (0.1 % (v/v) Formic Acid in 95:5 (v/v) Water: Acetonitrile) and B (0.1 % (v/v) Formic Acid in 95:5 (v/v) Acetonitrile: Water) according to the gradients outlined in Table 2 below. Retention times RT are reported in minutes.

Table 2

[00184] NMR was also used to characterise final compounds. NMR spectra were obtained on a Bruker AVIII 400 Nanobay with 5mm BBFO probe. Optionally, compound Rf values on silica thin layer chromatography (TLC) plates were measured.

[00185] Compound purification was performed by flash column chromatography on silica or by preparative LCMS. LCMS purification was performed using a Waters 3100 Mass detector in positive and negative electrospray mode (m/z: 150-800) with a Waters 2489 UV/Vis detector. Samples were eluted at a flow rate of 20mL/min on a XBridge™ prep C18 5μΜ OBD 19x100mm column with a mobile phase system composed of A (0.1 % (v/v) Formic Acid in Water) and B (0.1 % (v/v) Formic Acid in Acetonitrile) according to the gradient outlined in Table 3 below.

Time (min) %A %B

0 90 10 1 .5 90 10

1 1 .7 5 95

13.7 5 95

14 90 90

15 90 90

Table 3

[00186] Chemical names in this document were generated using mol2nam - Structure to Name Conversion by OpenEye Scientific Software. Starting materials were purchased from commercial sources or synthesised according to literature procedures.

[00187] Intermediate 1 : 2-Oxocyclopentanecarbonitrile

Potassium fe/f-butoxide (41 .51 g, 370mmol) was added to a stirred solution of adiponitrile (42.06ml_, 370mmol) and THF (600ml_) at room temperature under a nitrogen atmosphere. After stirring for 8 hours H2SO4 (19.72ml_, 370mmol) (1 M solution) was added to the reaction and the resulting mixture allowed to stir for 18 hours at room temperature. After this time sat. aq. NhUCI (600ml_) was added and the resulting mixture was extracted with EtOAc (2 x 500ml_). The combined organic layers were dried over Na2S04 and solvent removed in vacuo to give 2-oxocyclopentanecarbonitrile (29.31 g, 269mmol, 73% yield) as a yellow oil.

Ή NMR (CDCI3, 400MHz) δ/ppm: 3.20 (1 H, dd, J = 8.4Hz, 10.2Hz), 2.15-2.60 (5H, bm), 1 .92 (1 H, m).

MS Method 2: RT: 0.76 min, m/z 1 10.1 [M+H] ⁺

[00188] Intermediate 2: 5-(4-aminophenyl)-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4- d]pyrimidin-4-amine

2e 2d 2c Scheme 1

[00189] Intermediate 2a: benzyl N-(4-aminophenyl)carbamate

Benzyl (2,5-dioxopyrrolidin-1 -yl) carbonate (46.09g, 184.95mmol) in MeCN (200ml_) was added dropwise to a stirred solution of p-phenylenediamine (7.25ml_, 184.95mmol) in MeCN (200ml_) at room temperature. The reaction was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and Na2C03 and EtOAc added. The layers were separated and solvent removed under reduced pressure. The crude oil was stirred in Εί∑0 and precipitate filtered off, and the filtrate was concentrated in vacuo to yield benzyl N-(4-aminophenyl)carbamate

(40.5g,167.17mmol, 90% yield) as a red solid.

MS Method 2: RT: 0.95 min, m/z 243.1 [M+H] ⁺

[00190] Intermediate 2b: benzyl N-[4-(cyanomethylamino)phenyl]carbamate

Benzyl N-(4-aminophenyl)carbamate (37g, 152.72mmol) and Ν,Ν-diisopropylethylamine (26.60ml_, 152.72mmol) were added to THF (100ml_). Bromoacetonitrile (1 1 .7ml_, 168.00mmol) was added slowly and the reaction mixture stirred at reflux overnight. The reaction mixture was allowed to cool to room temperature and EtOAc (500ml_) added. The organic layer was washed with water

(250ml_). The aqueous layer was extracted with EtOAc (3 x 100ml_). Organic layers were combined, washed with brine (50ml_), dried over Na2S04, filtered and concentrated under reduced pressure. The crude mixture was stirred in ether and the solid filtered to yield benzyl N-[4- (cyanomethylamino)phenyl]-carbamate (22.04g, 78.35mmol, 51 % yield) as a light brown solid. MS Method 2: RT: 2.06 min, m/z 282.1 [M+H] ⁺

[00191] Intermediate 2c: benzyl N-[4-[(2-cyanocyclopenten-1 -yl)- (cyanomethyl)amino]phenyl]carbamate

To a solution of benzyl N-[4-(cyanomethylamino)phenyl]carbamate (48.2g, 171 .34mmol) in toluene (350ml_), 2-oxocyclopentanecarbonitrile (19.63g, 179.91 mmol) and p-toluenesulfonic acid monohydrate (2.95g, 17.13mmol) were added. The reaction was heated at reflux for 3 hours under Dean-Stark conditions. Sat. aq. NaHC03 and EtOAc were added to the reaction mixture, the organic layer was separated, washed with brine and dried over Na2S04. The solvent was removed under reduced pressure to give benzyl N-[4-[(2-cyanocyclopenten-1 -yl)-

(cyanomethyl)amino]phenyl]carbamate (46.79g, 125.64mmol, 73% yield) as a brown oil which was used in the next step without further purification.

MS Method 2: RT: 2.46 min, m/z 373.2 [M+H] ⁺

[00192] Intermediate 2d: benzyl N-[4-(3-amino-2-cyano-5,6-dihydro-4H-cyclopenta[b]pyrrol- 1 -yl)phenyl]carbamate

Sodium fe/ -butoxide (15.16g, 135.1 1 mmol) was added to a stirred solution of benzyl N-[4-[(2- cyanocyclopenten-1 -yl)-(cyanomethyl)amino]phenyl]carbamate (47.92g, 128.68mmol) and tert- butanol (400ml_) at room temperature. The reaction was heated to 80 °C for 30 minutes and then cooled to room temperature and sat. aq. NhUCI (600ml_) added. The resulting mixture was extracted with EtOAc (2 x 500ml_). The combined organic layers were washed with brine (500ml_), dried over Na2S04 and solvent removed in vacuo to give benzyl N-[4-(3-amino-2-cyano-5,6-dihydro-4H- cyclopenta[b]pyrrol-1 -yl)phenyl]carbamate (47.92g, 128.68mmol, 100% yield) which was used directly in the next step without further purification.

MS Method 2: RT: 1 .79 min, m/z 373.2 [M+H] ⁺

[00193] Intermediate 2e: benzyl N-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4- d]pyrimidin-5-yl)phenyl]carbamate

Formamidine acetate (53.59g, 514.72mmol) was added to a stirred solution of EtOH (300ml_) and benzyl N-[4-(3-amino-2-cyano-5,6-dihydro-4H-cyclopenta[b]pyrrol-1 -yl)phenyl]carbamate (47.92g, 128.68mmol) at room temperature. The reaction was heated to 80 °C and stirred for 3 hours. The reaction was then cooled to room temperature and solvent removed in vacuo. The residue was partitioned between sat. aq. NaHC03 and EtOAc (500mL/500ml_). The organic layer was separated and the aqueous layer extracted with EtOAc (500ml_). The combined organic layers were dried over Na2S04 and concentrated in vacuum to give benzyl N-[4-(4-amino-7,8-dihydro-6H- cyclopenta[2,3]pyrrolo[2,4-d]pyrimidin-5-yl)phenyl]carbamate (51 .40g, 128.68mmol, 100% yield) as a brown solid which was used in the next step without further purification.

MS Method 2: RT: 1 .38 min, m/z 400.3 [M+H] ⁺

[00194] Intermediate 2: 5-(4-aminophenyl)-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4- d]pyrimidin-4-amine

Benzyl N-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]py rimidin-5-yl)phenyl]carbamate (51 .40g, 128.68mmol) was dissolved in EtOAc (500ml_) and the resulting solution stirred at room temperature. Palladium, 10 wt. % on carbon powder, dry (5.00g, 46.98mmol) was added and then the reaction was fitted with a hydrogen balloon and subjected to 3 x vacuum/hydrogen cycles and then left to stir under a hydrogen atmosphere for 72 hours. After this time the reaction had not gone to completion and more palladium (2.5g) was added. A fresh hydrogen balloon was fitted and the reaction was subjected to 3 x vacuum/hydrogen cycles and allowed to stir for a further 48 hours. After this time the reaction was filtered through celite and the filtrate concentrated in vacuo. The residue was the purified by column chromatography using an eluent of 0-15% methanol in dichloromethane to give 5-(4-aminophenyl)-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4- d]pyrimidin-4- amine (6.60g, 24.88mmol, 19% yield) as a light brown solid. The yield of 19% was over 4 steps. Ή NMR (DMSO-d6, 400MHz) δ/ppm: 8.08 (1 H, s), 7.10 (2H, d, J = 6.4Hz), 6.67 (2H, d, J = 6.4Hz), 5.50 (2H, s), 5.42 (2H, br s), 2.78 (2H, m), 2.67 (2H, m), 2.48 (2H, m).

MS Method 2: RT: 0.99 min, m/z 266.2 [M+H] ⁺

[00195] Intermediate 3: 5-(4-amino-3-methoxy-phenyl)-7,8-dihydro-6H- cyclopenta[2,3]pyrrolo[2,4-d]pyrimidin-4-amine

Scheme 2

[00196] Intermediate 3a: benzyl N-(2-methoxy-4-nitro-phenyl)carbamate

[00197] Benzyl chloroformate (32.80ml_, 229.80mmol) was added to a stirred mixture of 2- methoxy-4-nitroaniline (27.60g, 164.1 mmol), magnesium oxide (5.62g, 139.51 mmol) and acetone (350mL) at room temperature under a nitrogen atmosphere. The reaction was stirred at room temperature for 18 hours, after which time it had gone around 50%. More benzyl chloroformate was added (20ml_) and the reaction allowed to stir for a further 24 hours. After this time it had gone to completion. Water (300ml_) was added which caused a yellow solid to crash out which was filtered and dried. This solid still contained some magnesium salts so it was added to EtOAc (300ml_). This mixture was heated to 50 °C and solid (magnesium salts) filtered off. Some crystals crashed out of the filtrate and these were collect and dried to give product A (12.46g) as yellow crystals. The rest of the filtrate was concentrated in vacuo and the resulting solid dried to give product B (27.30g) as a yellow solid. This gave, in total, benzyl N-(2-methoxy-4-nitro-phenyl)carbamate (39.76g,

131 .53mmol, 80% yield).

MS Method 2: RT: 2.69min, m/z 303.1 [M+H] ⁺ , 301 .1 [M-H] ^"

[00198] Intermediate 3b: benzyl N-(4-amino-2-methoxy-phenyl)carbamate

[00199] Benzyl N-(2-methoxy-4-nitro-phenyl)carbamate (39.76g, 131 .53mmol) was stirred in EtOAc (500ml_) at room temperature and platinum on carbon, 5 wt. % loading (5.00g) added. The reaction was fitted with a hydrogen balloon and subjected to 3 x vacuum/hydrogen cycles and then allowed to stir under a hydrogen atmosphere for 24 hours. It was then filtered through celite and the filtrate concentrated in vacuo to give benzyl N-(4-amino-2-methoxy-phenyl)carbamate (34.50g, 126.70mmol, 96% yield) as a brown solid which was used in the next step without further purification.

MS Method 2: RT: 1 .32min, m/z 273.1 [M+H] ⁺

[00200] Intermediate 3c: benzyl N-[4-(cyanomethylamino)-2-methoxy-phenyl]carbamate

[00201] Bromoacetonitrile (7.03ml_, 100.99mmol) was added to a stirred solution of benzyl N-(4- amino-2-methoxy-phenyl)carbamate (25.00g, 91 .81 mmol) and THF (500ml_) at room temperature under a nitrogen atmosphere. The reaction was then heated to 66 °C and stirred for 18 hours. It was then cooled to room temperature and most of the solvent removed in vacuo. Water (500ml_) was then added and this was extracted with EtOAc (2 x 300ml_). The combined orgainc layers were washed with sat. aq. NhUCI (500ml_), sat. aq. NaHCOs (500ml_), brine (500ml_), dried over Na ₂ S0 ₄ and solvent removed in vacuo to give benzyl N-[4-(cyanomethylamino)-2-methoxy- phenyl]carbamate (24.26g, 77.92mmol, 85% yield) as a brown solid which was used in the next step without further purification.

MS Method 2: RT: 1 .62min, m/z 312.0 [M+H] ⁺

[00202] Intermediate 3d: benzyl N-[4-[(2-cyanocyclopenten-1 -yl)-(cyanomethyl)amino]-2- methoxy-phenyl]carbamate

[00203] p-Toluenesulfonic acid monohydrate (1 .48g, 7.79mmol) was added to a stirred solution of 2-oxocyclopentanecarbonitrile (9.35g, 85.71 mmol), benzyl N-[4-(cyanomethylamino)-2-methoxy- phenyl]carbamate (24.26g, 77.92mmol) and toluene (600ml_) at room temperature. The reaction was then heated at reflux under Dean-Stark conditions for 4 hours. It was then cooled to room temperature and solvent removed until about 100ml_ remained. Sat. aq. NaHC03 (500ml_) was then added and the resultant mixture was extracted with EtOAc (2 x 400ml_). The combined organic extracts were washed with brine (500ml_) and dried over Na2S04. Solvent was removed in vacuo to give benzyl N-[4-[(2-cyanocyclopenten-1 -yl)-(cyanomethyl)amino]-2-methoxy-phenyl]carbamate (31 .36g, 77.92mmol, 100% yield) as a brown solid which was used directly in the next step without further purification.

MS Method 2: RT: 2.61 , m/z 403.3 [M+H] ⁺ , 401 .3 [M-H] ^"

[00204] Intermediate 3e: benzyl N-[4-(3-amino-2-cyano-5,6-dihydro-4H-cyclopenta[b]pyrrol- 1 -yl)-2-methoxy-phenyl]carbamate

[00205] Sodium fe/ -butoxide (7.49g, 77.92mmol) was added to a stirred solution of benzyl N-[4- [(2-cyanocyclopenten-1 -yl)-(cyanomethyl)amino]-2-methoxy-phenyl]carbamate (31 .36g, 77.92mmol) and fe/ -butanol (300ml_) at room temperature under a nitrogen atmosphere. The reaction was then heated to 80 °C for 2 hours and then cooled to room temperature. Sat. aq. NhUCI (500ml_) was added and the resulting mixture extracted with EtOAc (2 x 300ml_). The combined orgainc layers were washed with sat. aq. NaHC03 (500ml_), brine (500ml_), dried over Na2S04 and solvent removed in vacuo to give benzyl N-[4-(3-amino-2-cyano-5,6-dihydro-4H-cyclopenta[b]pyrrol-1 -yl)-2- methoxy-phenyl]carbamate (31 .36g, 77.92mmol, 100% yield) as a brown solid which was used directly in the next step without further purification.

MS Method 2: RT: 2.64min, m/z 444.2 [M+MeCN] ⁺ , 401 .3 [M-H] ^" [00206] Intermediate 3f: benzyl N-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4- d]pyrimidin-5-yl)-2-methoxy-phenyl]carbamate

[00207] Formamidine acetate (32.45g, 31 1 .68mmol) was added to a stirred solution of EtOH (250ml_) and benzyl N-[4-(3-amino-2-cyano-5,6-dihydro-4H-cyclopenta[b]pyrrol-1 -yl)-2-methoxy- phenyljcarbamate (31 .36g, 77.92mmol) at room temperature under a nitrogen atmosphere. The reaction was heated to 80 °C and stirred for 3 hours and then cooled to room temperature. Solvent was removed in vacuo and the residue partitioned between sat. aq. NaHC03 (500ml_) and EtOAc (500ml_). The organic layer was separated and the aqueous layer extracted with EtOAc (300ml_). The combined organic layers were dried over Na2S04 and solvent removed in vacuo to give benzyl N-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]py rimidin-5-yl)-2-methoxy- phenyljcarbamate (33.46g, 77.92mmol, 100% yield) as a brown solid which was used in the next step without further purification.

MS Method 2: RT: 1 .81 , m/z 430.3 [M+H] ⁺

[00208] Intermediate 3: 5-(4-amino-3-methoxy-phenyl)-7,8-dihydro-6H- cyclopenta[2,3]pyrrolo[2,4-d]pyrimidin-4-amine

[00209] Palladium , 10 wt. % on carbon powder, dry (3.00g) was added to a stirred solution of benzyl N-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]py rimidin-5-yl)-2-methoxy- phenyljcarbamate (23.00g, 53.55mmol) and EtOAc (500ml_) at room temperature under a nitrogen atmosphere. The reaction was fitted with a hydrogen balloon and subjected to 3 x vacuum/hydrogen cycles and then left to stir under a hydrogen atmosphere for 48 hours. After this time another 3g of palladium was added and a fresh hydrogen balloon fitted and the reaction subjected to 3 x vacuum/hydrogen cycles and left to stir under a hydrogen atmosphere for a further 48 hours. After this time the reaction was filtered through celite and the filter cake washed with EtOAc (100ml_). The filtrate was concentrated in vacuo and the residue purified by column chromatography using an eluent of 0-100% EtOAc in heptane followed by 0-15% methanol in dichloromethane to give 5-(4- amino-3-methoxy-phenyl)-7,8-dihydro-6H-cyclopenta[2,3]pyrrol o[2,4-d]pyrimidin-4-amine (6.45g, 21 .84mmol, 40% yield).

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 8.09 (1 H, s), 8.88 (1 H, d, J = 2.0Hz), 6.77 (1 H, dd, J = 8.0Hz, 2.0Hz), 6.72 (1 H, d, J = 8.0Hz), 5.54 (2H, br s), 5.09 (2H, s), 3.79 (3H, s), 2.78 (2H, m), 2.71 (2H, m), 2.45 (2H, m).

MS Method 2: RT: 1 .01 , m/z 296.1 [M+H] ⁺

[00210] Intermediate 4: 4-oxotetrahydrofuran-3-carbonitrile

[00211] To a solution of potassium te/ -butoxide (24.91 g, 222.03mmol) in THF (200ml_) at 0 °C was added methyl glycolate (20.00ml_, 259mmol) dropwise. The mixture was left to stir for 10 minutes before adding acrylonitrile (14.62ml_, 222mmol) dropwise. The reaction then allowed to warm to room temperature and left to stir for 3 hours. Water and EtOAc were added to the reaction mixture and the layers separated. The aqueous layer as then acidified to pH1 with 1 M HCI and extracted twice with EtOAc. The combined organic layers were then washed with brine, dried over Na2S04 and then passed through a hydrophobic frit before being concentrated under reduced pressure to afford 4-oxotetrahydrofuran-3-carbonitrile (10.29g, 93mmol, 42% yield) as a yellow solid.

Ή NMR (CDC , 400MHz) δ/ppm: 4.65 (1 H, t, J = 9.3Hz), 4.26 (1 H, t, J = 9.3Hz), 4.18 (1 H, d, J = 17.5Hz), 4.02 (1 H, d, J = 17.5Hz), 3.61 (1 H, t, J = 9.3Hz).

[00212] Intermediate 5

formamidine acetate, EtOH

Scheme 3

[00213] Intermediate 5a: Benzyl N-[4-[(4-cyano-2,5-dihydrofuran-3-yl)- (cyanomethyl)amino]phenyl]carbamate

[00214] To benzyl N-[4-(cyanomethylamino)phenyl]carbamate (30.00g, 106.64mmol) in toluene (350ml_) was added 4-oxotetrahydrofuran-3-carbonitrile (12.44g, 1 1 1 .98mmol) and 1 -methyl-4- methylsulfonyl-benzene hydrate (1 .94g, 10.31 mmol). The reaction mixture was stirred at reflux for 4 hours. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure to give a brown oil which was dissolved in EtOAc (l OOOmL), washed with sat. NaHC03 (500ml_), brine (100ml_), dried over Na2S04, filtered and concentrated under reduced pressure to give benzyl N-[4-[(4-cyano-2,5-dihydrofuran-3-yl)-

(cyanomethyl)amino]phenyl]carbamate (38.57g,103.09mmol, 96% yield) as a brown oil which was used in the next step without further purification.

MS Method 2: RT: 2.28 min, m/z 374.2 [M+H] ⁺ [00215] Intermediate 5b: Benzyl N-[4-(3-amino-2-cyano-4,6-dihydrofuro[3,4-b]pyrrol-1 - yl)phenyl]carbamate

[00216] Benzyl N-[4-[(4-cyano-2,5-dihydrofuran-3-yl)-(cyanomethyl)amino]phe nyl]carbamate (29.1 Og, 77.73mmol) and potassium fe/ -butoxide (8.72g, 77.73mmol) in fe/ -butanol (450mL) were stirred at 80 °C for 1 hour. The reaction mixture was allowed to cool to room temperature and diluted with EtOAc (l OOOmL). The organics were washed with sat. NhUCI (500ml_) and brine (100ml_), dried (Na2S04), filtered and concentrated under reduced pressure to give the benzyl N-[4- (3-amino-2-cyano-4,6-dihydrofuro[3,4-b]pyrrol-1 -yl)phenyl]carbamate (16.12g, 43.00mmol, 55% yield) as a brown oil which was used without further purification.

MS Method 2: RT: 2.16 min, m/z 416.2 [M+MeCN] ⁺

[00217] Intermediate 5c: benzyl N-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-d]pyrimidin-5- yl)phenyl]carbamate

[00218] To a solution of benzyl N-[4-(3-amino-2-cyano-4,6-dihydrofuro[3,4-b]pyrrol-1 - yl)phenyl]carbamate (16.12g, 43.00mmol) in EtOH (250ml_) was added formamidine acetate (17.93g, 172.23mmol) and the mixture headed to 80 °C for 2h. The reaction was allowed to cool to room temperature before EtOAc and sat. aq. NaHC03 were added. The layers were separated and the organics were washed with brine before being dried over Na2S04, filtered and the solvent removed under reduced pressure to afford benzyl N-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4- d]pyrimidin-5-yl)phenyl]carbamate (13.50g, 33.63mmol, 78% yield) as a brown solid/foam which was used in the next step without further purification.

MS Method 2: RT: 1 .43 min, m/z 402.1 [M+H] ⁺

[00219] Intermediate 5: 5-(4-aminophenyl)-6,8-dihydrofuro[2,3]pyrrolo[2,4-d]pyrimidi n-4- amine

[00220] A solution of benzyl N-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-d]pyrimidin-5- yl)phenyl]carbamate (13.50g, 33.63mmol) in EtOAc (250ml_) was evacuated and back filled 3 times with nitrogen before adding palladium on carbon, 10 wt. % loading (1 .35g). The reaction mixture was once again evacuated and back filled 3 times with nitrogen before evacuating and back filling 3 times with hydrogen. The reaction mixture was left to stir overnight. Subsequent LCMS indicated no product had formed. MeOH (50ml_) was added to aid solubility as well as more palladium on carbon, 10 wt. % loading (1 .35g) and the reaction back filled 3 times with nitrogen before evacuating and back filling 3 times with hydrogen. The reaction was left to stir at room temperature for 48 hours. The reaction was then evacuated and back filled 3 times with nitrogen before filtering through a plug of celite. The filtrate was concentrated under reduced pressure to afford a brown oil. The material was purified by column chromatography using an eluent of 0-10% MeOH in DCM to give 5-(4-aminophenyl)-6,8-dihydrofuro[2,3]pyrrolo[2,4-d]pyrimidi n-4-amine (1 .77g, 6.62mmol, 20% yield) as a light brown solid.

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 8.14 (1 H, s), 7.15 (2H, d, J = 6.4Hz), 6.66 (2H, d, J = 6.4Hz), 5.62 (2H, br s), 5.54 (2H, s), 5.04 (2H, m), 4.86 (2H, m).

MS Method 2: RT: 0.82 min, m/z 268.1 [M+H] ⁺ [00221] Intermediate 6

formamidine acetate, EtOH

Scheme 4

[00222] Intermediate 6a: benzyl N-[4-[(4-cyano-2,5-dihydrofuran-3-yl)-(cyanomethyl)amino]- 2-methoxy-phenyl]carbamate

[00223] A solution of p-toluenesulfonic acid (1 .01 g, 5.33mmol), benzyl N-[4-(cyanomethylamino)- 2-methoxy-phenyl]carbamate (16.53g, 53.09mmol) and 4-oxotetrahydrofuran-3-carbonitrile (8.85g, 79.64mmol) was heated to 140 °C under Dean-Stark conditions for 1 .5 hours. The reaction mixture was cooled to room temperature and further 4-oxotetrahydrofuran-3-carbonitrile (2.50g) was added and the reaction mixture heated to 140 °C under Dean-Stark conditions for a further 2 hours. The reaction mixture was allowed to cool to room temperature and sat. aq. NaHC03 solution and EtOAc were added and the layers separated. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried over anhydrous Na2S04, filtered and the solvent removed in vacuo to afford benzyl N-[4-[(4-cyano-2,5-dihydrofuran-3-yl)-

(cyanomethyl)amino]-2-methoxy-phenyl]carbamate (21 .47g, 53.10mmol, 100% yield) as a viscous brown oil.

MS Method 2: RT: 1 .76 min, m/z 405.3 [M+H] ⁺

[00224] Intermediate 6b: benzyl N-[4-(3-amino-2-cyano-4,6-dihydrofuro[3,4-b]pyrrol-1 -yl)-2- methoxy-phenyl]carbamate

[00225] A solution of benzyl N-[4-[(4-cyano-2,5-dihydrofuran-3-yl)-(cyanomethyl)amino]-2- methoxy-phenyl]carbamate (21 .47g, 53.09mmol) and potassium fe/f-butoxide (5.96g, 53.09mmol) in fe/ -butanol (250ml_) was stirred at 80 °C for 45 minutes. The reaction mixture was cooled to room temperature and sat. aq. NhUCI solution and EtOAc were added and the layers separated. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried over anhydrous Na2S04 and the solvent removed in vacuo to afford benzyl N-[4-(3-amino-2- cyano-4,6-dihydrofuro[3,4-b]pyrrol-1 -yl)-2-methoxy-phenyl]carbamate (16.86g, 41 .69mmol, 78% yield).

MS Method 2: RT: 1 .73 min, m/z 405.3 [M+H] ⁺

[00226] Intermediate 6c: benzyl N-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-d]pyrimidin-5- yl)-2-methoxy-phenyl]carbamate

[00227] To a solution of benzyl N-[4-(3-amino-2-cyano-4,6-dihydrofuro[3,4-b]pyrrol-1 -yl)-2- methoxy-phenyl]carbamate (16.86g, 41 .69mmol) in EtOH (200ml_) was added formamidine acetate (17.36g, 166.76mmol) and the reaction mixture was heated to 80 °C for 2h. The reaction mixture was cooled to room temperature and solvent was removed under reduced pressure. EtOAc and sat. aq. NaHC03 were added. The layers were separated and the aqueous was then extracted with EtOAc. The combined organics were then washed with brine and dried over Na2S04. The material was filtered and concentrated under reduced pressure to afford benzyl N-[4-(4-amino-6,8- dihydrofuro[2,3]pyrrolo[2,4-d]pyrimidin-5-yl)-2-methoxy-phen yl]carbamate (13.52g, 31 .34mmol, 75% yield) as a brown solid which was used in the next step without further purification.

MS Method 2: RT: 1 .33 min, m/z 432.3 [M+H] ⁺

[00228] Intermediate 6: 5-(4-amino-3-methoxy-phenyl)-6,8-dihydrofuro[4,5]pyrrolo[1 ,2- d]pyrimidin-4-amine

[00229] To a degassed solution of benzyl N-[4-(4-amino-6,8-dihydrofuro[4,5]pyrrolo[1 ,2- d]pyrimidin-5-yl)-2-methoxy-phenyl]carbamate (13.52g, 31 .34mmol) in methanol (100ml_)

(evacuated and back filled 3 times with nitrogen) was added palladium on carbon, 10 wt. % loading (0.61 g). The flask was then evacuated and then back filled 3 times with hydrogen. The reaction mixture was left to stir at room temperature overnight. The reaction mixture was then filtered through celite and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography using an eluent of 0-5% MeOH in DCM to give 5-(4-amino-3-methoxy- phenyl)-6,8-dihydrofuro[4,5]pyrrolo[1 ,2-d]pyrimidin-4-amine (3.84g, 12.91 mmol, 41 % yield) as a light brown solid.

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 8.14 (1 H, s), 6.96 (1 H, d, J = 2.4Hz), 6.84 (1 H, dd, J = 8.2Hz, 2.3Hz), 6.73 (1 H, d, J = 8.2Hz), 5.66 (2H, br s), 5.13 (2H, s), 5.06 (2H, t, J = 3.0Hz), 4.90 (2H, s), 3.80 (3H, s).

MS Method 2: RT: 0.89 min, m/z 298.0 [M+H] ⁺

[00230] Intermediate 7

Scheme 5

[00231] Intermediate 7a: tert-butyl N-(3-fluoro-4-nitro-phenyl)carbamate

[00232] DMAP (1 .17g, 9.6mmol) was added to a stirred suspension of 3-fluoro-4-nitroaniline (15.01 g, 96.14mmol) and di-te/ -butyl dicarbonate (20.98g, 96.13mmol) in DCM (300ml_) under nitrogen. The reaction was stirred at room temperature overnight under nitrogen. The reaction was then heated to 60 °C for a further 14 hours under nitrogen. It was then cooled to room temperature and concentrated in vacuo to afford a black oil which was taken up in EtOAc (200ml_) and washed with sat. aq. NhUCI (200ml_), sat. aq. NaHCOs (200ml_) and brine (200ml_). The organic layer was dried over Na2S04, filtered and concentrated in vacuo to afford a black oil which was purified by column chromatography, eluting with 10% EtOAc in heptane, to give fe/ -butyl N-(3-fluoro-4-nitro- phenyl)carbamate as a yellow solid (19.78g, 68.17mmol, 71 % yield).

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 10.29 (1 H, s), 8.13 (1 H, t, J = 9.0Hz), 7.62 (1 H, dd, J = 2.2Hz, 14.6Hz), 7.38 (1 H, dd, J = 1 .9Hz, 9.2Hz), 1 .50 (9H, s).

MS Method 2: RT: 1 .82 min, m/z 257.1 [M+H] ⁺

[00233] Intermediate 7b: tert-butyl N-(4-amino-3-fluoro-phenyl)carbamate

[00234] To a degassed solution of fe/ -butyl N-(3-fluoro-4-nitro-phenyl)carbamate (19.78g, 68.17mmol) in EtOAc (150ml_) under nitrogen was added palladium, 10 wt. % on carbon powder, dry (6.29g, 5.91 mmol). The mixture was degassed and put under a hydrogen atmosphere and stirred overnight at room temperature. The reaction was then filtered through celite. The celite was washed through with EtOAc (200ml_). The combined organic filtrate was then concentrated in vacuo to afford a pink oil (16.22g, 62.39mmol, 92% yield).

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 9.02 (1 H, br s,), 7.17 (1 H, br d, J = 13.6Hz,), 6.90 (1 H, br d, J = 10.0Hz,), 6.64 (1 H, dd, J = 8.6Hz, 10.2Hz,), 4.74 (2H, br s,), 1 .44 (9H, s).

MS Method 2: RT: 1 .42 min, m/z 227.2 [M+H] ⁺

[00235] Intermediate 7c: fert-butyl N-[4-(benzyloxycarbonylamino)-3-fluoro- phenyl]carbamate

[00236] A solution of fe/ -butyl N-(4-amino-3-fluoro-phenyl)carbamate (17.47g, 68.17mmol) in DCM (250mL) was chilled to 0 °C under nitrogen. Then benzyl chloroformate (10.50ml_, 73.55mmol) was added followed by Ν,Ν-diisopropylethylamine (12.9mL, 74.06mmol) and the reaction was slowly allowed to warm up to room temperature overnight under nitrogen. The reaction was then concentrated in vacuo to afford a pink solid. The solid was then partitioned between water (200ml_) and EtOAc (150ml_). The aqueous layer was then extracted with EtOAc (2 x 150ml_). The combined organic layers were then washed with brine (200ml_) dried over Na2S04, filtered and concentrated in vacuo to afford fe/ -butyl N-[4-(benzyloxycarbonylamino)-3-fluoro-phenyl]carbamate as an off white solid (22.93g, 61 .10mmol, 90% yield).

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 9.51 (1 H, br s,), 9.21 (1 H, br s), 7.31 -7.45 (7H, m), 7.14 (1 H, dd, J = 1 .6Hz, 8.8Hz,), 5.12 (2H, s), 1 .47 (9H, s).

MS Method 2: RT: 1 .90 min, m/z 359.2 [M-H] ^"

[00237] Intermediate 7d: Benzyl N-(4-amino-2-fluoro-phenyl)carbamate hydrochloride

[00238] To a mixture of fe/ -butyl N-[4-(benzyloxycarbonylamino)-3-fluoro-phenyl]carbamate (22.94g, 61 .10mmol) in 1 ,4-dioxane (40ml_) at 0 °C was added 4M HCI in 1 ,4-dioxane (31 mL, 124mmol). The reaction was stirred at 0 °C slowly allowing the reaction to warm to room

temperature. Additional 4M HCI in 1 ,4-dioxane (26.5ml_, 106mmol) was added and the reaction was left stirring at room temperature overnight under nitrogen. Overnight the reaction had become a solid suspension. DCM (200ml_) was added to the reaction and the resulting mixture was left stirring at room temperature under nitrogen. Additional 4M HCI in 1 ,4-dioxane (20ml_, 80mmol) was added and the reaction was left stirring at room temperature overnight under nitrogen. The mixture was then concentrated in vacuo to afford benzyl N-(4-amino-2-fluoro-phenyl)carbamate hydrochloride as a cream solid (18.1 g, 61 .1 mmol, 100% yield).

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 9.25 (1 H, br s), 7.28-7.45 (6H, m), 6.78-6.88 (2H, m), 5.12 (2H, s), 2.50 (2H, m).

MS Method 2: RT: 1 .42 min, m/z 261 .2 [M+H] ⁺

[00239] Intermediate 7e: Benzyl N-[4-(cyanomethylamino)-2-fluoro-phenyl]carbamate

[00240] To a suspension of benzyl N-(4-amino-2-fluoro-phenyl)carbamate hydrochloride (19.01 g, 64.08mmol) and bromoacetonitrile (6.70ml_, 96.19mmol) in DCM (300ml_) was added N,N- diisopropylethylamine (33.50ml_, 192.33mmol) at room temperature under nitrogen. The reaction was then heated to 80 °C overnight under nitrogen. Additional bromoacetonitrile (6.7ml_,

96.19mmol) and Ν,Ν-diisopropylethylamine (33.5ml_, 192.33mmol) was added and the reaction was left at 60 °C overnight under nitrogen. Additional bromoacetonitrile (6.7ml_, 96.19mmol) was added and the reaction was left at 60 °C. After 3 hours the reaction was cooled to room temperature, then washed with sat. aq. NhUCI solution (3 x 200 ml_) and brine, dried over Na2S04, filtered and concentrated in vacuo to afford a brown oil which was purified by column chromatography eluting with 25-50% EtOAc in heptane to give benzyl N-[4-(cyanomethylamino)-2-fluoro-phenyl]carbamate as an off white solid (16.80g, 46.03mmol, 72% yield).

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 8.99 (1 H, br s), 7.31 -7.42 (5H, m,), 7.19-7.24 (1 H, m), 6.59 (1 H, dd, J = 2.5Hz, 12.9Hz), 6.50 (1 H, dd, J = 2.2Hz, 8.7Hz,), 6.45 (1 H, t, J = 6.8Hz), 5.10 (2H, s), 4.27 (2H, d, J = 6.8Hz).

MS Method 2: RT: 1 .59 min, m/z 298.2 [M-H] ^"

[00241] Intermediate 7f: Benzyl N-[4-[(2-cyanocyclopenten-1 -yl)-(cyanomethyl)amino]-2- fluoro-phenyl]carbamate

[00242] A mixture of benzyl N-[4-(cyanomethylamino)-2-fluoro-phenyl]carbamate (4.43g, 14.79mmol), 2-oxocyclopentanecarbonitrile (1 .62g, 14.81 mmol) and p-toluenesulfonic acid monohydrate (0.25g, 1 .47mmol) in toluene (25ml_) was heated to 150 °C with under Dean Stark conditions for 3 hours. Additional 2-oxocyclopentanecarbonitrile (1 .65g, 15.16mmol) was added and the reaction was stirred for 2 hours left at 150 °C under Dean-Stark conditions. The reaction was then cooled to room temperature and concentrated in vacuo to afford a brown oil. The brown oil was partitioned between sat. aq. NaHCC (50ml_) and EtOAc (50ml_). The aqueous layer was then extracted with EtOAc (2 x 50ml_), washed with brine (3 x 50ml_), dried over Na2S04, filtered and concentrated in vacuo to afford benzyl N-[4-[(2-cyanocyclopenten-1 -yl)-(cyanomethyl)amino]-2- fluoro-phenyl]carbamate as a brown oil (8.34g, 13.46mmol, 91 % yield).

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 9.64 (1 H, s), 7.77 (1 H, t, J = 8.8Hz), 7.13-7.45 (7H, m), 5.17 (2H, s), 4.84 (2H, s), 2.59-2.63 (2H, m), 2.50-2.55 (2H, m), 1 .83-1 .91 (2H, m).

MS Method 2: RT: 1 .79 min, m/z 391 .3 [M+H] ⁺

[00243] Intermediate 7g: Benzyl N-[4-(3-amino-2-cyano-5,6-dihydro-4H-cyclopenta[b]pyrrol- 1 -yl)-2-fluoro-phenyl]carbamate

[00244] To a solution of benzyl N-[4-[(2-cyanocyclopenten-1 -yl)-(cyanomethyl)amino]-2-fluoro- phenyl]carbamate (8.32g, assume 14.79mmol) in fe/ -butanol (60ml_) was added potassium tert- butoxide (2.4g, 21 .41 mmol). The resulting mixture was heated to 80 °C under nitrogen for 2 hours. The reaction was cooled to room temperature and diluted with sat. aq. NH4CI (240ml_) and extracted with EtOAc (3 x 100ml_). The combined organic layers were then washed with brine (2 x 100ml_), dried over Na2S04, filtered and concentrated in vacuo to afford a brown oil (7.84g, 14.67mmol, 99%).

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 9.56 (1 H, s), 7.70 (1 H, t, J = 8.7Hz), 7.27-7.45 (6H, m), 7.16- 7.19 (1 H, m), 5.35 (2H, s), 5.17 (2H, s), 2.66-2.70 (2H, m), 2.46-2.50 (2H, m), 2.27-2.36 (2H, m). MS Method 2: RT: 1 .84 min, m/z 391 .3 [M+H] ⁺

[00245] Intermediate 7h: Benzyl N-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4- d]pyrimidin-5-yl)-2-fluoro-phenyl]carbamate [00246] To a solution of benzyl N-[4-(3-amino-2-cyano-5,6-dihydro-4H-cyclopenta[b]pyrrol-1 -yl)-2- fluoro-phenyl]carbamate (5.77g, 14.79mmol) in EtOH (150mL) was added formamidine acetate (8.36g, 80.32mmol). The reaction was then heated to 90 °C for 2.5 hours under nitrogen. The reaction was cooled to room temperature. Then concentrated in vacuo to afford a brown residue which was partitioned between DCM (200ml_) and sat. aq. NaHC03 (200ml_). The aqueous layer was extracted with DCM (2 x 200ml_). The combined organic layers were then washed with brine (200 ml_), dried over Na2S04, filtered and concentrated in vacuo to afford benzyl N-[4-(4-amino-7,8- dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]pyrimidin-5-yl)-2-fl uoro-phenyl]carbamate 6.17g,

14.79mmol, 100% yield) as a brown solid which was taken directly on to the next step without further purification.

Ή (DMSO-d6, 400MHz) δ/ppm: 9.71 (1 H, br s), 8.14 (1 H, s), 7.86 (1 H, t, J = 8.8Hz), 7.30-7.46 (6H, m), 7.18-7.22 (1 H, m), 5.69 (2H, br s,), 5.20 (2H, s), 2.77-2.80 (4H, m), 2.42-2.50 (2H, m).

MS Method 2: RT: 1 .35 min, m/z 418.3 [M+H] ⁺

[00247] Intermediate 7: 5-(4-amino-3-fluoro-phenyl)-7,8-dihydro-6H- cyclopenta[2,3]pyrrolo[2,4-d]pyrimidin-4-amine

[00248] To a degassed mixture of benzyl N-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4- d]pyrimidin-5-yl)-2-fluoro-phenyl]carbamate (6.17g, 14.79mmol) in EtOAc (50ml_) and MeOH (50ml_) under nitrogen was added. Palladium, 10 wt. % on carbon powder, dry (1 .78g, 1 .68mmol). The resulting mixture was then degassed again and put under a hydrogen atmosphere and stirred for 18 hours. The reaction was then filtered through a pad of celite, the celite was washed through with MeOH (200ml_). The organic filtrate was then concentrated in vacuo to afford a red brown foam which was purified by column chromatography, eluting with 0-5% MeOH in DCM, to give 5-(4- amino-3-fluoro-phenyl)-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo [2,4-d]pyrimidin-4-amine as an off white solid (2.30g, 7.70mmol, 52% yield).

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 8.09 (1 H, s), 7.20 (1 H, dd, J = 2.2Hz, 1 1 .6Hz,), 6.95-6.98 (1 H, m), 6.86 (1 H, dd, J = 8.6Hz, 9.8Hz,), 5.51 (2H, br s), 5.48 (2H, br s), 2.75-2.79 (2H, m), 2.66- 2.71 (2H, m), 2.39-2.46 (2H, m).

MS Method 2: RT: 1 .04 min, m/z 284.2 [M+H] ⁺

[00249] Intermediate 8

Scheme 6

[00250] Intermediate 8a: Methyl 2-(4-aminophenyl)acetate

[00251] 4-Aminophenylacetic acid (10.00g, 66.16mmol) in MeOH (350ml_) was stirred and cone. H2SO4 (3.88ml_, 72.77mmol) was added dropwise. This was stirred and heated to 50 °C overnight, then allowed to cool to room temperature and concentrated in vacuo. It was then diluted with water, neutralised solid with Na2C03, then extracted with DCM. The organic layer was dried over Na2S04 and concentrated to afford methyl 2-(4-aminophenyl)acetate (9.75g, 59.02mmol, 89% yield) MS Method 2: RT: 0.60 min, m/z 165.9 [M+H] ⁺

[00252] Intermediate 8b: Methyl 2-[4-(cyanomethylamino)phenyl]acetate

[00253] To a solution of methyl 2-(4-aminophenyl)acetate (7.68g, 46.49mmol) and

bromoacetonitrile (3.72ml_, 53.47mmol) in THF (70ml_) was added DIPEA (9.31 mL, 53.47mmol) and the resulting mixture was stirred at 80 °C overnight. The reaction was allowed to cool to room temperature and sat. aq. NhUCI and EtOAc were added and the layers separated. The organic layer was washed with sat. aq. NhUCI solution, brine, dried over Na2S04, filtered and the solvent removed in vacuo to afford methyl 2-[4-(cyanomethylamino)phenyl]acetate (9.50g, 46.50mmol, 100% yield) as a brown solid which was used in the next step without any further purification.

Ή NMR (CDCI3, 400MHz) δ/ppm: 7.21 (2H, d, J = 9.2Hz), 6.70 (2H, d, J = 9.2Hz), 4.12 (2H, d, J = 7.2Hz), 4.00 (1 H, m), 3.71 (2H, s), 3.57 (3H, s).

MS Method 2: RT: 1 .32 min, m/z 205.0 [M+H] ⁺ [00254] Intermediate 8c: Methyl 2-[4-[(2-cyanocyclopenten-1 -yl)- (cyanomethyl)amino]phenyl]acetate

[00255] To a solution of methyl 2-[4-(cyanomethylamino)phenyl]acetate (30.91 g, 151 .34mmol) and 2-oxocyclopentanecarbonitrile (24.77g, 227.01 mmol) in toluene (200mL) was added p- toluenesulfonic acid monohydrate (2.88g, 15.13mmol) and the resulting mixture was refluxed under Dean-Stark conditions overnight. The reaction mixture was allowed to cool to room temperature and the solvent was removed in vacuo. EtOAc and sat. aq. NaHC03 were added and the layers separated. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried over Na2S04, filtered and the solvent removed in vacuo. The crude material was purified by column chromatography (0-100% EtOAc/heptane) to afford methyl 2-[4-[(2- cyanocyclopenten-1 -yl)-(cyanomethyl)amino]phenyl]acetate (15.00g, 50.79mmol, 33% yield) as a brown oil.

MS Method 2: RT: 2.03 min, m/z 296.1 [M+H] ⁺

[00256] Intermediate 8d: Methyl 2-[4-(3-amino-2-cyano-5,6-dihydro-4H-cyclopenta[b]pyrrol- 1 -yl)phenyl]acetate

[00257] A solution of methyl 2-[4-[(2-cyanocyclopenten-1 -yl)-(cyanomethyl)amino]phenyl]acetate (8.00g, 27.09mmol) and sodium te/ -butoxide (2.08g, 21 .67mmol) in te/ -butanol (100ml_) was heated at 80 °C for 1 hour. Sodium fe/ -butoxide (1 .00g) was added and the mixture stirred for 1 hour. Further sodium fe/ -butoxide (1 .00g) was added and the mixture was heated to 80 °C for 1 hour. The reaction mixture was allowed to cool to room temperature and EtOAc and sat. aq. NhUCI solution was added and the layers separated. The organic layer was washed with brine and then dried over anhydrous Na2S04, filtered and the solvent removed in vacuo to afford methyl 2-[4-(3- amino-2-cyano-5,6-dihydro-4H-cyclopenta[b]pyrrol-1 -yl)phenyl]acetate (8.00g, 27.09mmol, 100% yield) .

MS Method 2: RT: 2.03 min, m/z 296.1 [M+H] ⁺ , 337.1 [M+MeCN+H] ⁺

[00258] Intermediate 8e: Methyl 2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4- d]pyrimidin-5-yl)phenyl]acetate

[00259] A solution of methyl 2-[4-(3-amino-2-cyano-5,6-dihydro-4H-cyclopenta[b]pyrrol-1 - yl)phenyl]acetate (8.00g, 27.09mmol) and formamidine acetate (1 1 .28g, 108.35mmol) in EtOH (150ml_) was stirred at 80 °C overnight. The solvent was removed in vacuo and water and EtOAc were added and the layers separated. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried over anhydrous Na2S04, filtered and the solvent removed in vacuo. The crude residue was purified by column chromatography (0-100% EtOAc/heptane followed by 0-20% MeOH/DCM) to afford methyl 2-[4-(4-amino-7,8-dihydro-6H- cyclopenta[2,3]pyrrolo[2,4-d]pyrimidin-5-yl)phenyl]acetate (1 .40g, 4.34mmol, 16% yield).

MS Method 2: RT: 2.03 min, m/z 323.1 [M+H] ⁺

[00260] Intermediate 8: 2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]py rimidin- 5-yl)phenyl]acetic acid [00261] A solution of methyl 2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]py rimidin- 5-yl)phenyl]acetate (1 .40g, 4.34mmol) in EtOH (10ml_) and 1 M NaOH (10ml_, 10mmol) was stirred for 3 hours. The EtOH was removed in vacuo and 1 M HCI (15ml_) was added and the precipitate filtered to afford 2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]py rimidin-5- yl)phenyl]acetic acid (940mg, 3.05mmol, 70% yield).

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 8.14 (1 H, s), 7.45 (2H, d, J = 8.8Hz), 7.38 (2H, d, J = 8.8Hz), 5.50 (2H, br s), 3.67 (2H, s), 2.78 (4H, m), 2.45 (2H, m), exchangeable acid proton not visible. MS Method 2: RT: 1 .09 min, m/z 309.1 [M+H] ⁺

[00262] Intermediate 9

9g 9f 9e

Scheme 7

[00263] Intermediate 9a: Diethyl 2-(2-methoxy-4-nitro-phenyl)propanedioate

[00264] A solution of diethyl malonate (5.32ml_, 35.06mmol) and caesium carbonate (20.94g, 64.28mmol) in DMF (6ml_) was heated to 70 °C under nitrogen for 30 minutes. 3-Methoxy-4- fluoronitrobenzene (5.00g, 29.22mmol) was then added and the mixture turned from a cloudy white solution to a purple solution. The reaction was stirred for 90 minutes. The reaction mixture was cooled to room temperature and was diluted with EtOAc and water. The aqueous layer was brought to a neutral pH with acetic acid and extracted with EtOAc. The combined organic layers were washed with water, brine and dried over Na2S04, filtered and concentrated in vacuo to afford diethyl 2-(2-methoxy-4-nitro-phenyl)propanedioate as a red oil which partially solidified overnight (9.05g, 29.22mmol, 100% yield).

Ή NMR (CDC , 400MHz) δ/ppm: 7.79 (1 H, dd, J = 8.3Hz, 2.2Hz), 6.67 (1 H, J = 2.2Hz), 7.47 (1 H, d, J = 8.3Hz), 5.08 (1 H, s), 4.24 - 4.10 (4H, m), 3.87 (3H, s), 1 .28 - 1 .13 (6H, m). MS Method 2: RT: 1 .78 min, m/z 312 [M+H] ⁺

[00265] Intermediate 9b: 2-(2-methoxy-4-nitro-phenyl)acetic acid

[00266] NaOH (6M, 15.72ml_, 94.35mmol) was added to a solution of diethyl 2-(2-methoxy-4-nitro- phenyl)propanedioate (9.79g, 31 .45mmol) in MeOH (30ml_). The reaction mixture was stirred at 50 °C for 16 hours. The reaction was quenched with the addition of sat. aq. citric acid and then extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2S04 and solvent removed in vacuo to give 2-(2-methoxy-4-nitro-phenyl)acetic acid as a yellow solid of (6.19g, 29.31 mmol, 93% yield).

Ή NMR (CDC , 400MHz) δ/ppm: 7.76 (1 H, dd, J = 8.3Hz, 2.3Hz), 7.66 (1 H, d, J = 2.3Hz), 7.27 (1 H, d, J = 8.2Hz), 3.87 (3H, s), 3.68 (2H, s), 3.62 (1 H, s).

MS Method 2: RT: 1 .33 min, m/z 212.0 [M+H] ⁺

[00267] Intermediate 9c: Methyl 2-(2-methoxy-4-nitro-phenyl)acetate

[00268] H2SO4 (0.16ml_, 3.04mmol) was added to a solution of 2-(2-methoxy-4-nitro-phenyl)acetic acid (6.41 g, 30.35mmol) in MeOH (200ml_). The reaction mixture was stirred at 50 °C for 1 hour. The reaction mixture was concentrated in vacuo, sat. aq. NaHCC was added to the oil to achieve a neutral pH. The aqueous layer was extracted with EtOAc (3 x 50ml_) and the combined organic layers were washed with twice brine. The organic layers were dried over Na2S04 and solvent removed in vacuo to give methyl 2-(2-methoxy-4-nitro-phenyl)acetate (5.72g, 25.40mmol, 86% yield) as an orange solid.

Ή NMR (CDCI3, 400MHz) δ/ppm: 7.76 (1 H, dd, J = 8.3Hz, 2.2Hz), 7.65 (1 H, d, J = 2.2Hz), 7.27 (1 H, d, J = 8.3Hz), 3.86 (3H, s), 3.70 - 3.61 (5H, m).

MS Method 2: RT: 1 .57 min, m/z 226.0 [M+H] ⁺

[00269] Intermediate 9d: Methyl 2-(4-amino-2-methoxy-phenyl)acetate

[00270] Palladium, 10% wt. on carbon powder, dry (270mg, 2.54mmol) was added to a solution of methyl 2-(2-methoxy-4-nitro-phenyl)acetate (5.72g, 25.4mmol) in EtOAc (150ml_). The reaction mixture was placed under a H2 atmosphere and stirred at room temperature for 19 hours. The reaction mixture was filtered through celite and washed with MeOH. The filtrate was concentrated in vacuo to give methyl 2-(4-amino-2-methoxy-phenyl)acetate (4.82g, 24.69mmol, 97% yield).

Ή NMR (CDCI3, 400MHz) δ/ppm: 6.88 (1 H, d, J = 7.7Hz), 6.26 - 6.18 (2H, m), 3.69 (3H, s), 3.60 (3H, s), 3.55 (2H, br s), 3.45 (2H, s).

MS Method 2: RT: 0.91 min, m/z 196.0 [M+H] ⁺

[00271] Intermediate 9e: Methyl 2-[4-(cyanomethylamino)-2-methoxy-phenyl]acetate

[00272] DIPEA (8.12ml_, 46.61 mmol) was added to a solution of methyl 2-(4-amino-2-methoxy- phenyl)acetate (9.1 g, 46.61 mmol) and bromoacetonitrile (3.25ml_, 46.61 mmol) in THF (5ml_) at room temperature. The reaction solution was heated at 80 °C overnight. The reaction mixture was cooled to room temperature and the bulk THF was removed in vacuo to give a brown gum. The brown gum was diluted with EtOAc (200ml_). The organic layer was washed twice with sat. aq. NH4CI, brine, dried over Na2S04 and solvent removed under reduced pressure to give a brown solid of methyl 2-[4-(cyanomethylamino)-2-methoxy-phenyl]acetate (10.90g, 46.61 mmol, 100% yield). Ή NMR (CDC , 400MHz) δ/ppm: 7.00 (1 H, d, J = 8.0Hz), 6.26 - 6.15 (2H, m), 4.03 (2H, s), 3.73 (3H, s), 3.61 (3H, s), 3.48 (2H, s), exchangeable NH not seen.

MS Method 2: RT: 1.38 min, m/z 235.1 [M+H] ⁺

[00273] Intermediate 9f: Methyl 2-[4-[(2-cyanocyclopenten-1 -yl)-(cyanomethyl)amino]-2- methoxy-phenyl]acetate

[00274] 2-Oxocyclopentanecarbonitrile (5.94g, 54.47mmol) and p-toluenesulfonic acid

monohydrate (0.94g, 4.95mmol) were added to a solution of methyl 2-[4-(cyanomethylamino)-2- methoxy-phenyl]acetate (1 1 .6g, 49.52mmol) in toluene (150ml_). The reaction mixture was refluxed for 18 hours under Dean-Stark conditions. The reaction mixture was cooled to room temperature and concentrated in vacuo. EtOAc (150ml_) was added and the organic layer washed twice with sat. aq. NaHC03 and brine. The organic layer was dried over Na2S04 and solvent removed in vacuo to give methyl 2-[4-[(2-cyanocyclopenten-1 -yl)-(cyanomethyl)amino]-2-methoxy-phenyl]acetate

(12.47g, 38.33mmol, 77% yield) as a dark brown solid.

Ή NMR (CDCb, 400MHz) δ/ppm: 7.16 (1 H, d, J = 8.0Hz), 6.75 (1 H, dd, J = 8.0Hz, 2.0 Hz), 6.69

(1 H, d, J = 2.0Hz), 4.60 (2H, s), 3.77 (3H, s), 6.64 (3H, s), 3.57 (2H, s), 2.62 (2H, t, J = 7.6Hz), 2.36

(2H, t, J = 7.6Hz), 1 .88 - 1 .73 (2H, m).

MS Method 2: RT: 1 .62 min, m/z 326.2 [M+H] ⁺

[00275] Intermediate 9g: 2-[4-(3-amino-2-cyano-5,6-dihydro-4H-cyclopenta[b]pyrrol-1 -yl)-2- methoxy-phenyl]acetic acid

[00276] Sodium te/ -butoxide (3.68g, 38.33mmol) was added to a solution of methyl 2-[4-[(2- cyanocyclopenten-1 -yl)-(cyanomethyl)amino]-2-methoxy-phenyl]acetate (12.47g, 38.33mmol) in fe/ -butanol (100ml_). The reaction was stirred at 80 °C for 1 hour. Sodium fe/ -butoxide (3.68g, 38.33mmol) was added and the reaction mixture was stirred at 80 °C for 1 hour. The reaction mixture was cooled to room temperature and sat. aq. NH4CI and EtOAc were added. The organic layer was separated and then extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2S04. The aqueous layers were acidified with HCI (1 M) to a pH ~3/4 and extracted with EtOAc. This organic layer was dried over Na2S04 and concentrated in vacuo. The dried organic layers were all combined and concentrated in vacuo to give 2-[4-(3-amino-2- cyano-5,6-dihydro-4H-cyclopenta[b]pyrrol-1 -yl)-2-methoxy-phenyl]acetic acid (8.04g, 25.85mmol, 67% yield) as a dark brown oil.

MS Method 2: RT: 1 .44 min, m/z 312.2 [M+H] ⁺

[00277] Intermediate 9: 2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]py rimidin- 5-yl)-2-methoxy-phenyl]acetic acid

[00278] Formamidine acetate (10.62g, 102.01 mmol) was added to a suspension of 2-[4-(3-amino- 2-cyano-5,6-dihydro-4H-cyclopenta[b]pyrrol-1 -yl)-2-methoxy-phenyl]acetic acid (7.94g, 25.50mmol) in EtOH (100ml_) and was stirred at 80 °C for 2.5 hours. The reaction was cooled to room temperature and solvent removed in vacuo. The material was dissolved in EtOAc (150ml_) and H2O (150ml_), the biphasic mixture was separated. The aqueous layer was concentrated in vacuo and the resulting precipitate filtered and dried to give 2-[4-(4-amino-7,8-dihydro-6H- cyclopenta[2,3]pyrrolo[2,4-d]pyrimidin-5-yl)-2-methoxy-pheny l]acetic acid (902mg, 2.66mmol, 10% yield) as a brown solid.

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 8.14 (1 H, s), 7.79 (1 H, s), 7.33 (1 H, d, J = 7.9Hz), 7.01 (1 H, d, J = 2.0Hz), 6.93 (1 H, dd, J = 7.9Hz, 2.0Hz), 5.54 (2H, br s), 3.79 (3H, s), 3.41 (1 H, s), 2.87 - 2.74 (4H, m), 2.49 - 2.41 (2H, m), exchangeable proton of the acid group not observed.

MS Method 2: RT: 1 .13 min, m/z 339.2 [M+H] ⁺

[00279] Intermediate 10

Scheme 8

[00280] Intermediate 10a: benzyl N-(3-fluoro-4-nitro-phenyl)carbamate

[00281] To a solution of 3-fluoro-4-nitro-aniline (5.00g, 32.03mmol) in DCM (100ml_) at 0 °C under nitrogen was slowly added Ν,Ν-diisopropylethylamine (5.83ml_, 33.50mmol) followed by benzyl chloroformate (4.79ml_, 33.53mmol) in DCM (100ml_). The reaction was allowed to warm to room temperature, and was left stirring overnight under nitrogen. LCMS analysis demonstrated little conversion to the desired product. The reaction mixture was heated to 40 °C for 4 hours. An additional eq. of DIPEA and benzyl chloroformate were added and the reaction heated at 40 °C overnight. LCMS analysis demonstrated more conversion to desired product. An additional eq of DIPEA and benzyl chloroformate were added and the reaction heated at 40 °C overnight. LCMS analysis demonstrated more conversion to desired product. An additional equivalent of DIPEA and benzyl chloroformate were added and the reaction heated at 40 °C over the weekend. The reaction mixture was cooled to room temperature and water and EtOAc added. The layers were separated and the aqueous extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2S04 and solvent removed under reduced pressure. Εί∑0 was added and the reaction mixture stirred for 30 minutes. The precipitate was filtered off to yield benzyl N-(3-fluoro-4-nitro- phenyl)carbamate (3.09g, 10.65mmol, 33% yield) as a brown solid.

MS Method 2: RT: 1 .82 min, m/z 291 .2 [M+H] ⁺

[00282] Intermediate 10b: benzyl N-(4-amino-3-fluoro-phenyl)carbamate

[00283] Platinum on carbon, 5 wt. % loading (3.09g, 15.85mmol) and EtOAc (50ml_) were added to a solution of benzyl N-(3-fluoro-4-nitro-phenyl)carbamate (4.60g, 15.85mmol) in EtOAc (50ml_). The reaction mixture was degassed and charged with hydrogen and stirred at room temperature overnight. The reaction mixture was filtered through a pad of celite, the solvent was removed under reduced pressure to yield benzyl N-(4-amino-3-fluoro-phenyl)carbamate (3.70g, 14.22mmol, 89% yield) that was taken through to the next stage without further purification.

MS Method 2: RT: 1 .51 min, m/z 261 .2 [M+H] ⁺

[00284] Intermediate 10c: benzyl N-[4-(cyanomethylamino)-3-fluoro-phenyl]carbamate

[00285] Bromoacetonitrile (1 .09ml_, 15.64mmol) and Ν,Ν-diisopropylethylamine (2.48ml_, 14.22mmol) were added to a solution of benzyl N-(4-amino-3-fluoro-phenyl)carbamate (3.70g, 14.22mmol) in THF (50ml_), the reaction was heated at 80 °C for 2 days. The reaction mixture was cooled to room temperature and sat. aq NhUCI and EtOAc were added. The layers were separated and the aqueous layer extracted with EtOAc (3 x 50ml_). The combined organic layers were washed with brine, dried over Na2S04 and solvent removed under reduced pressure to yield benzyl N-[4- (cyanomethylamino)-3-fluoro-phenyl]carbamate (4.29g, 14.22mmol, 100% yield) as a brown oil. MS Method 2: RT: 1 .68 min, m/z 298.2 [M-H] ^"

[00286] Intermediate 10d: benzyl N-[4-[(2-cyanocyclopenten-1 -yl)-(cyanomethyl)amino]-3- fluoro-phenyl]carbamate

[00287] p-Toluenesulfonic acid monohydrate (0.27g, 1 .43mmol) and 2- oxocyclopentanecarbonitrile (1 .72g, 15.77mmol) were added to a solution of benzyl N-[4- (cyanomethylamino)-3-fluoro-phenyl]carbamate (4.29g, 14.33mmol) in toluene (200ml_). The reaction mixture was heated at reflux under Dean Stark conditions overnight. The reaction was then concentrated to dryness and the residue was taken up in EtOAc (100ml_) and sat. aq. NaHC03 added. The aqueous layer was extracted with EtOAc and the combined organic layers washed with brine, dried over Na2S04 and solvent removed under reduced pressure to yield benzyl N-[4-[(2- cyanocyclopenten-1 -yl)-(cyanomethyl)amino]-3-fluoro-phenyl]carbamate (5.62g, 14.33mmol, 100% yield) as a brown oil which was continued through to the next stage without further purification. MS Method 2: RT: 1 .80 min, m/z 391 .3 [M+H] ⁺

[00288] Intermediate 10e: Benzyl N-[4-(3-amino-2-cyano-5,6-dihydro-4H-cyclopenta[b]pyrrol- 1 -yl)-3-fluoro-phenyl]carbamate

[00289] Sodium fe/ -butoxide (1 .50g, 15.57mmol) was added to a solution of benzyl N-[4-[(2- cyanocyclopenten-1 -yl)-(cyanomethyl)amino]-3-fluoro-phenyl]carbamate (6.08g, 15.57mmol) in tert- butanol (100ml_) and stirred at 80 °C for 2 hours. LCMS analysis demonstrated the reaction had run to completion. Saturated aqueous NhUCI was added and the aqueous extracted with EtOAc (3x100ml_). The combined organic layers were washed with brine, dried over Na2S04 and solvent removed under reduced pressure to yield benzyl N-[4-(3-amino-2-cyano-5,6-dihydro-4H- cyclopenta[b]pyrrol-1 -yl)-3-fluoro-phenyl]carbamate (4.38g, 1 1 .22mmol, 72% yield) as a crude brown oil.

MS Method 2: RT: 1 .84 min, m/z 391 .3 [M+H] ⁺

[00290] Intermediate 10f: Benzyl N-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4- d]pyrimidin-5-yl)-3-fluoro-phenyl]carbamate

[00291] Formamidine acetate (1 .17g, 1 1 .22mmol) was added to a solution of benzyl N-[4-(3- amino-2-cyano-5,6-dihydro-4H-cyclopenta[b]pyrrol-1 -yl)-3-fluoro-phenyl]carbamate (4.38g, 1 1 .22mmol) in EtOH (100mL). The reaction was stirred at 80 °C for 2 hours. Sat. aq. NaHCOs and EtOAc were then added to the reaction mixture and the organic layer separated. The organic layer was washed with brine and dried over Na2S04 and the solvent was removed under reduced pressure to yield benzyl N-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]py rimidin-5-yl)- 3-fluoro-phenyl]carbamate (2.50g, 6.00mmol, 53% yield).

MS Method 2: RT: 1 .44 min, m/z 418.3 [M+H] ⁺

[00292] Intermediate 10: 5-(4-amino-2-fluoro-phenyl)-7,8-dihydro-6H- cyclopenta[2,3]pyrrolo[2,4-d]pyrimidin-4-amine

[00293] Palladium, 10 wt. % on carbon powder, dry (867mg, 8.14mmol) was added to a degassed solution of benzyl N-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]py rimidin-5-yl)-3- fluoro-phenyl]carbamate (3.40g, 8.14mmol) in EtOAc (50ml_). The reaction mixture was degassed again, charged with hydrogen and stirred at room temperature overnight. LCMS analysis demonstrated the reaction had not run to completion. Additional palladium, 10 wt. % on carbon powder, dry (867mg, 8.14mmol) was added and the reaction mixture was stirred at room temperature for 3 days under hydrogen. The reaction mixture was filtered through a pad of celite and washed through with EtOAc, the solvent was removed under reduced pressure to yield 5-(4- amino-2-fluoro-phenyl)-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo [2,4-d]pyrimidin-4-amine (1 .50g, 5.30mmol, 65% yield) as a brown oil/solid.

Ή NMR (CDC , 400MHz) δ/ppm: 8.32 (1 H, s), 7.17 (1 H, m), 6.56 (2H, m), 5.10 (2H, br s), 4.1 1

(2H, br s), 2.95 (2H, m), 2.65 (4H, m).

MS Method 2: RT: 1 .05 min, m/z 284.2 [M+H] ⁺

[00294] Intermediate 11 : Potassium 2-(4-pyridyl)acetate

[00295] Ethyl 4-pyridylacetate (0.94ml_, 6.1 1 mmol) was dissolved in EtOH (15 mL) and distilled water (1 15μΙ_, 6.42mmol) and heated to 60 °C. A solution of potassium fe/ -butoxide (720mg, 6.42mmol) in EtOH (5ml_) was then added dropwise and the reaction was stirred at 60 °C overnight. The EtOH was removed in vacuo and the resulting residue triturated with ether and dried in the vac oven to yield potassium 2-(4-pyridyl)acetate (538mg, 3.92mmol, 64% yield) as a colourless solid. Ή NMR (DMSO-d6, 400MHz) δ/ppm: 8.34 (2H, d, J = 4.0Hz), 7.18 (2H, d, J = 4.0Hz), 3.17 (2H, s). MS Method 2: RT: 0.42 min, m/z 138.1 [M+H] ⁺ (free acid)

[00296] Intermediate 12: Potassium 2-(3-pyridyl)acetate

[00297] Ethyl-3-pyridylacetate (0.82ml_, 5.41 mmol) was dissolved in EtOH (15ml_) and distilled water (1 15μΙ_, 6.42mmol) and heated to 60 °C. A solution of potassium fe/ -butoxide (637mg, 5.68mmol) in EtOH (5ml_) was then added dropwise and the reaction was stirred at 60 °C overnight. The ethanol was removed in vacuo and the resulting residue triturated with ether and dried in the vacuum oven to yield potassium 2-(3-pyridyl)acetate (410mg, 2.34mmol, 43% yield) as a colourless solid, which was carried through directly to the next stage without further purification.

[00298] Ή NMR (DMSO-d6, 400MHz) δ/ppm: 8.35 (1 H, d, J = 1 .6Hz), 8.28 (1 H, m), 7.58 (1 H, t, J = 6.0Hz), 7.21 (1 H, dd, J = 8.0Hz, 4.8Hz), 3.41 (1 H, s), 3.16 (2H, s).

[00299] Intermediate 13

O

H

13a 13

Scheme 9

[00300] Intermediate 13a: Ethyl 2-morpholinoacetate

[00301] Morpholine (261 μΙ_, 2.99mmol) was added to a stirred solution of ethyl bromoacetate (332μΙ_, 2.99mmol) and DIPEA (639μΙ_, 3.59mmol) in THF (5ml_) which was then refluxed for 120 minutes. The product was partitioned between sat. aq. NaHC03 and EtOAc, the aqueous fraction was back extracted with EtOAc. The combined organic fractions were washed with brine, dried over

Na2S04 and the solvents removed under vacuum to yield ethyl 2-morpholinoacetate (41 1 mg,

2.37mmol, 79% yield) as a yellow oil.

Ή NMR (CDC , 400MHz) δ/ppm: 4.21 (2H, q, J = 7.0Hz), 3.86-3.73 (4H, m), 3.22 (2H, s), 2.64-

2.57 (4H, m), 1 .30 (3H, t, J = 7.0Hz).

MS Method 2: RT: 0.35 min, m/z 174.2 [M+H] ⁺

[00302] Intermediate 13: Potassium 2-morpholinoacetate

[00303] 6M KOH (337μΙ_, 2.03mmol) was added to a stirred solution of ethyl 2-morpholinoacetate (351 mg, 2.03mmol) and EtOH (15ml_) and the reaction stirred for 3 hours at room temperature. The solvents were removed under vacuum to yield potassium 2-morpholinoacetate (314mg, 1 .71 mmol, 84% yield) as a pale yellow solid.

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 3.57-3.51 (4H, m), 2.62 (2H, s), 2.43-2.36 (4H, m).

[00304] Intermediate 14

[00305] Intermediate 14 is made in an analogous manner to Intermediate 13, Scheme 9, substituting pyrrolodine for morpholine.

[00306] Intermediate 14a: Ethyl 2-pyrrolidin-1 -ylacetate

[00307] Pyrrolidine (249μΙ_, 2.99mmol) was added to a stirred solution of ethyl bromoacetate (332μΙ_, 2.99mmol) and DIPEA (639μΙ_, 3.59mmol) in THF (5ml_) which was then refluxed for 3 hours. The product was partitioned between sat. aq. NaHC03 and EtOAc, the aqueous fraction was back extracted with EtOAc. The combined organic fractions were washed with brine, dried over Na2S04 and the solvents removed under vacuum to yield ethyl 2-pyrrolidin-1 -ylacetate (342mg, 2.17mmol, 72% yield) as a colourless oil.

Ή NMR (CDC , 400MHz) δ/ppm: 4.21 (2H, q, J = 7.2Hz), 3.35 (2H, s), 2.68-2.63 (4H, m), 1 .86-

1 .82 (4H, m), 1 .30 (3H, t, J = 7.2Hz).

MS Method 2: RT: 0.30 min, m/z 158.1 [M+H] ⁺

[00308] Intermediate 14: Potassium 2-pyrrolidin-1 -ylacetate

[00309] 6M KOH (248μΙ_, 1 .49mmol) was added to a stirred solution of ethyl 2-pyrrolidin-1 - ylacetate (234mg, 1 .49mmol) and EtOH (15ml_) and the reaction stirred for 3 hours at room temperature. A further 1 .5 equivalents of 6N KOH were added after NMR showed incomplete reaction. The solvents were removed under vacuum to yield potassium 2-pyrrolidin-1 -ylacetate (249mg, 1 .49mmol, 100% yield) as a yellow solid.

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 2.67 (2H, s), 2.44-2.40 (4H, m), 1 .62-1 .57 (4H, m)

MS Method 2: RT: 0.30 min, m/z 130.1 [M+H] ⁺

[00310] Intermediate 15

Scheme 10

[00311] Intermediate 15a: fert-Butyl 2-[4-(trifluoromethyl)-2-pyridyl]acetate

[00312] 2-Chloro-4-(trifluoromethyl)pyridine (0.35ml_, 2.75mmol), te/ -butyl acetate (0.55ml_,

4.13mmol) and 'BuXPhos Pd G1 (19mg, 0.03mmol) were combined in toluene (1 ml_), stirred, and cooled to 0 °C. LiHMDS 1 M in toluene (8.26ml_, 8.26mmol) was then added slowly. The mixture was slowly allowed to warm to room temperature and stirred overnight. Sat. aq. NH4CI solution (10ml_) was added and the mixture extracted with EtOAc (3 x 50ml_). The organics were combined, washed with brine (50ml_), dried over Na2S04, filtered then evaporated to dryness to give a brown oil. This was purified by column chromatography using an eluent of 0 to 40% EtOAc in heptane to give fe/f-butyl 2-[4-(trifluoromethyl)-2-pyridyl]acetate (220mg, 0.84mmol, 31 % yield) as a yellow oil. Ή NMR (CDC , 400MHz) δ/ppm: 8.56 (1 H, d, J = 5.2Hz), 7.35 (1 H, s), 7.23 (1 H, d, J = 5.2Hz), 3.67 (2H, s), 1 .25 (9H, s).

MS Method 2: RT: 1 .82 min, m/z 206.1 [M-'Bu+H] ⁺

Note: only the mass of the acid (205) is seen in the LCMS but f-butyl group can be seen in the NMR

[00313] Intermediate 15: 2-[4-(trifluoromethyl)-2-pyridyl]acetic acid hydrochloride

[00314] fe/f-Butyl 2-[4-(trifluoromethyl)-2-pyridyl]acetate (300mg, 1 .15mmol) was taken up in 4M HCI in dioxane (10.00mL, 40.00mmol) and stirred overnight at room temperature. The solvent was removed under reduced pressure to give 2-[4-(trifluoromethyl)-2-pyridyl]acetic acid hydrochloride (250mg, 0.96mmol, 90% yield) as an orange solid.

MS Method 2: RT: 1 .22 min, m/z 206.1 [M+H] ⁺ (free acid)

[00315] Intermediate 16

[00316] Intermediate 16, 17 and 18 are made in an analogous manner to Intermediate 15, Scheme 10, starting with a different aryl chloride.

[00317] Intermediate 16a: fert-Butyl 2-(6-methoxy-2-pyridyl)acetate

[00318] LiHMDS 1 M in toluene (10.45ml_, 10.45mmol) was added to a stirred solution of 2-chloro- 6-methoxy-pyridine (414μΙ_, 3.48mmol), fe/f-butyl acetate (706μΙ_, 5.22mmol) and 'BuXPhos Pd G1

(24mg, 0.03mmol) at 0 °C. The reaction was allowed to warm to room temperature stirred overnight.

NH4CI (15ml_) was added and the solution extracted with EtOAc (20ml_). The organic fraction was dried over Na2S04, the solvents were removed under reduced pressure and the residue purified via column chromatography using an eluent of 0-15% EtOAc in heptane to yield fe/f-butyl 2-(6- methoxy-2-pyridyl)acetate (547mg, 2.45mmol, 70% yield) as a yellow oil.

Ή NMR (CDCI3, 400MHz) δ/ppm: 8.35 (1 H, t, J = 7.2Hz), 6.65 (1 H, d, J = 7.2Hz), 6.45 (1 H, d, J =

8.0Hz), 3.75 (3H, s), 3.49 (2H, s), 1 .30 (9H, s).

MS Method 2: RT: 1 .79 min, m/z 168.0 [M-'Bu+H] ⁺

[00319] Intermediate 16: 2-(6-Methoxypyridin-1 -ium-2-yl)acetic acid chloride

[00320] fe/f-Butyl 2-(6-methoxy-2-pyridyl)acetate (130mg, 0.58mmol) was stirred in 4M HCI in dioxane (145μΙ_, 0.58mmol) at room temperature overnight. The solvents were removed under reduced pressure to yield 2-(6-methoxypyridin-1 -ium-2-yl)acetic acid chloride (74mg, 0.36mmol, 62% yield) as a colourless powder. [00321] Ή NMR (DMSO-d6, 400MHz) δ/ppm: 7.67 (1 H, dd, J = 8.4Hz, 7.2Hz), 6.93 (1 H, d, J = 7.2Hz), 6.71 (1 H, d, J = 8.4Hz), 3.82 (3H, s), 3.66 (2H, s), exchangeable carboxylic acid proton not seen.

MS Method 2: RT: 1 .03 min, m/z 168.1 [M+H] ⁺

[00322] Intermediate 17

[00323] Intermediate 17a: tert-Butyl 2-(5-methoxy-2-pyridyl)acetate

[00324] LiHMDS 1 M in toluene (7.98ml_, 7.98mmol) was added to a stirred solution of 2-bromo-5- methoxypyridine (0.35ml_, 2.66mmol), te/ -butyl acetate (0.54ml_, 3.99mmol) and 'BuXPhos Pd G1 (18mg, 0.03mmol) in a 3 neck flask evacuated/backfilled with nitrogen. The reaction mixture was allowed to stir for 24 hours at 0 °C. Sat. aq. NhUCI (6ml_) was added and the mixture was extracted three times with EtOAc. The combined organic fractions were dried over Na2S04, and the solvents were then removed in vacuo. The product was purified via column chromatography using an eluent of 10-20% EtOAc in heptane to yield te/ -butyl 2-(5-methoxy-2-pyridyl)acetate (201 mg, 0.90mmol, 34% yield) as a yellow oil.

Ή NMR (CDC , 400MHz) δ/ppm: 8.18-8.16 (1 H, m), 7.18-7.1 1 (2H, m), 3.79 (3H, s), 3.67 (2H, s), 1 .38 (9H, s).

MS Method 2: RT: 1 .30 min, m/z 224.2 [M+H] ⁺

[00325] Intermediate 17: 2-(5-Methoxypyridin-1 -ium-2-yl)acetic acid chloride

[00326] HCI in dioxane 4M (7.43ml_, 29.72mmol) was added to a stirred solution of te/ -butyl 2-(5- methoxy-2-pyridyl)acetate (663mg, 2.97mmol) and heated at 45 °C for 12 hours. The solvents were removed in vacuo to yield 2-(5-methoxypyridin-1 -ium-2-yl)acetic acid chloride (495mg, 2.43mmol, 82% yield) as a light yellow solid.

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 8.58 (1 H, d, J = 3.0 Hz), 8.07 (1 H, dd, J = 3.0Hz, 8.8Hz), 7.85 (1 H, d, J = 8.8Hz), 4.1 1 (2H, s), 3.97 (3H, s) exchangeable carboxylic acid proton not seen.

[00327] Intermediate 18

[00328] Intermediate 18a: tert-Butyl 2-(3-fluoro-5-methyl-2-pyridyl)acetate

[00329] 2-Chloro-3-fluoro-5-methylpyridine (500mg, 3.44mmol), te/ -butyl acetate (0.69ml_, 5.15mmol) and 'BuXPhos Pd G1 (23.59mg, 0.03mmol) were combined, stirred and cooled to 0 °C under a nitrogen atmosphere. LiHMDS (1 M in toluene) (10.31 ml_, 10.31 mmol) was added slowly and the mixture allowed to warm to room temperature and stirred overnight. Sat. aq, NH4CI (10ml_) was added and the resulting mixture extracted with EtOAc (3 x 20ml_). The organics were combined, washed with brine (20ml_), dried over Na2S04, filtered then evaporated to dryness to give a brown oil which was purified by column chromatography eluting with 0% to 50% EtOAc in heptane to give fe/f-butyl 2-(3-fluoro-5-methyl-2-pyridyl)acetate (440mg, 1 .90mmol, 57% yield) as a yellow oil.

Ή NMR (CDC , 400MHz) δ/ppm: 8.06 (1 H, s), 7.07 (1 H, d, J = 10.0Hz), 3.68 (2H, d, J = 2.4Hz),

2.21 (3H, s), 1 .31 (9H, s).

MS Method 2: RT: 1 .68 min, m/z 226.2 [M+H] ⁺

[00330] Intermediate 18: 2-(3-Fluoro-5-methyl-2-pyridyl)acetic acid

[00331] fe/ -Butyl 2-(3-fluoro-5-methyl-2-pyridyl)acetate (440mg, 1 .95mmol) was taken up in 4M HCI in dioxane (5.00ml_, 20mmol) and stirred at room temperature overnight. The solvent was removed under reduced pressure to give 2-(3-fluoro-5-methyl-2-pyridyl)acetic acid (330mg, 1 .95mmol, 100% yield) as a brown solid.

MS Method 2: RT: 1 .00 min, m/z 170.0 [M+H] ⁺

[00332] Intermediate 19

[00333] Intermediate 19 is made in an analogous manner to Intermediate 22 (from 22b), Scheme 1 1 , starting with a different aryl bromide.

[00334] Intermediate 19a: fert-Butyl 2-(1 -methylindol-5-yl)acetate

[00335] Zinc Powder (331 mg, 5.06mmol) and a stirrer bar was added to a dry 3-neck flask and the flask sealed and flushed with nitrogen. The zinc was then suspended in dry THF (12ml_), the suspension stirred and fe/ -butyl bromoacetate (0.67ml_, 4.56mmol) added to the vessel.

Diisobutylaluminium hydride (1 M in toluene) (0.08ml_, 0.51 mmol) was then added. Stirring was continued for 2 hours with heating to 40 °C, until the zinc had mostly dissolved giving a grey solution. This solution was then allowed to cool and to the vessel was added 5-bromo-1 -methyl- indole (531 mg, 2.53mmol) and QPhos (180mg, 0.25mmol). Nitrogen was then bubbled through the resulting stirred solution before tris(dibenzylideneacetone)dipalladium (0) (231 mg, 0.25mmol) was added, the vessel re-sealed, flushed with nitrogen again, and heated to reflux overnight. The solution was filtered through celite washing with MeOH and concentrated in vacuo. The product was isolated via column chromatography, eluting with 0 to 50% EtOAc in petroleum ether to give tert- butyl 2-(1 -methylindol-5-yl)acetate (218mg, 0.89mmol, 35% yield).

Ή NMR (CDCI3, 400MHz) δ/ppm: 7.44-7.42 (1 H, m), 7.21 -7.17 (1 H, m), 7.09-7.05 (1 H, m), 6.95 (1 H, d, J = 3.0Hz), 6.36 (1 H, d, J = 3.0Hz), 3.70 (3H, s), 3.53 (2H, s), 1 .36 (9H, s).

MS Method 2: RT: 1 .94 min, m/z 246.2 [M+H] ⁺

[00336] Intermediate 19: 2-(1 -Methylindol-5-yl)acetic acid

₃ [00337] A stirred solution of te/ -butyl 2-(1 -methylindol-5-yl)acetate (218mg, 0.89mmol) in 4M HCI in dioxane (4.44ml_, 17.77mmol) was heated at 45 °C for 6 hours, then concentrated in vacuo to yield 2-(1 -methylindol-5-yl)acetic acid (1 17mg, 0.62mmol, 70% yield).

Ή NMR (DMSO-d6, 400MHz) δ: 12.14 (1 H, s), 7.46-7.17 (3H, m), 7.06-7.02 (1 H, m), 6.39-6.35 (1 H, m), 3.77 (3H, s), 3.59 (2H, s).

MS Method 2: RT: 1 .35 min, m/z 190.0 [M+H] ⁺

[00338] Intermediate 20

[00339] Intermediate 20 is made in an analogous manner to Intermediate 13, Scheme 9, substituting a different amine and bromide.

[00340] Intermediate 20a: Ethyl 4-morpholinobutanoate

[00341] Morpholine (262μΙ_, 2.99mmol) was added to a stirred solution of ethyl 4-bromobutanoate (428μΙ_, 2.99mmol) and DIPEA (639μΙ_, 3.59mmol) in THF (5ml_) which was then refluxed for 16 hours. The product was partitioned between sat. aq. NaHC03 and EtOAc, the aqueous fraction was back extracted with EtOAc. The product was separated via SCX eluting with 2M Nhh in methanol. The combined organic fractions were washed with brine, dried over Na2S04 and the solvents removed under vacuum to yield ethyl 4-morpholinobutanoate (230mg, 1 .14mmol, 38% yield) as a yellow oil.

Ή NMR (CDC , 400MHz) δ/ppm: 4.06 (2H, q, J = 7.2Hz), 3.64 (4H, t, J = 4.0Hz), 2.37 (4H, t, J = 4.0Hz), 2.32-2.25 (4H, m), 1 .80-1 .71 (2H, m), 1 .19 (3H, t, J = 7.2Hz).

MS Method 2: RT: 0.46 min, m/z 202.1 [M+H] ⁺

[00342] Intermediate 20: Potassium 4-morpholinobutanoate

[00343] Potassium hydroxide (286μΙ_, 1 .71 mmol) was added to a stirred solution of ethyl 4- morpholinobutanoate (230mg, 1 .14mmol) and stirred for 3 hours at room temperature. The solvents were removed under vacuum and then product was separated via SCX eluting with 2M NH3 in methanol to give potassium 4-morpholinobutanoate (197mg, 0.93mmol, 82% yield).

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 3.55 (4H, t, J = 4.4Hz), 2.31 -2.26 (4H, m), 2.18 (2H, t, J = 7.6Hz), 1 .77 (2H, t, J = 7.6Hz), 1 .58-1 .49 (2H, m).

[00344] Intermediate 21

[00345] Intermediate 21 : 2-(1 -Benzyloxycarbonyl-4-piperidyl)acetic acid

[00346] 5 M NaOH (aq.) was added to a stirred solution of 2-piperidin-1 -ium-4-ylacetic acid chloride (1 .00g, 5.57mmol) in water (40ml_) at 0 °C until pH 12 was reached. Benzyl chloroformate (0.79ml_, 5.57mmol) was added dropwise to the solution. The mixture was stirred at room temperature for 24 hours and then the reaction mixture was extracted with Et20 (50ml_). The aqueous fraction was acidified to pH 4 with 1 M HCI, then extracted with EtOAc (3 x 20ml_). The combined organic layers were dried over Na2S04 and concentrated under vacuum to yield 2-(1 - Benzyloxycarbonyl-4-piperidyl)acetic acid (923mg, 3.33mmol, 60% yield) as an off-white solid.

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 12.09 (1 H, s), 7.41 -7.29 (5H, m), 5.06 (2H, s), 4.21 -4.04 (2H, m), 2.80-2.69 (2H, m), 2.15 (2H, d, J = 7.0Hz), 1 .89-1 .78 (1 H, m), 1 .73-1 .64 (2H, m), 1 .18-1 .08 (2H, m).

[00347] Intermediate 22

Scheme 11

[00348] Intermediate 22a: 1 -(5-bromoindolin-1 -yl)-2,2,2-trifluoro-ethanone

[00349] To a solution of 5-bromoindoline (2.00g, 10.10mmol) in DCM (40ml_) at 0 °C was added triethylamine (2.1 1 ml_, 15.15mmol) and trifluoroacetic anhydride (1 .68ml_, 12.12mmol). The reaction was allowed to warm to room temperature and left to stir for 3 hours. Water (80ml_) was added as well as DCM (80ml_) and the layers separated. The aqueous was extracted with DCM (50ml_). The organics were combined, washed with brine (50ml_), dried over Na2S04 and then passed through a hydrophobic frit. The solvent was removed under reduced pressure to afford 1 -(5-bromoindolin-1 - yl)-2,2,2-trifluoro-ethanone (3.01 g, 10.10mmol, 100% yield) as a brown/grey solid.

Ή NMR (CDC , 400MHz) δ/ppm: 8.10 (1 H, d, J = 9.2Hz), 7.41 (2H, m), 4.32 (2H, t, J = 8.4Hz), 3.28 (2H, t, J = 8.4Hz).

MS Method 2: RT: 1 .92 min, m/z 293.8/295.8 [M+H] ⁺

[00350] Intermediate 22b: 5-bromo-1 -(2,2,2-trifluoroethyl)indoline

[00351] To a solution of 1 -(5-bromoindolin-1 -yl)-2,2,2-trifluoro-ethanone (3.00g, 10.20mmol) in THF (6ml_) at 0 °C was added borane-THF complex (1 :1) (15.30ml_, 15.30mmol) . The solution was allowed to warm to room temperature before being heated at reflux overnight. The solution was then cooled to room temperature and quenched with aqueous NH4CI. Water and EtOAc were added, the aqueous layer was separated and extracted with further EtOAc. The organics were combined and washed with brine before being dried over Na2S04, filtered and concentrated under reduced pressure. The material was purified via column chromatography, using an eluent of 10 to 50% EtOAc in petroleum ether to give 5-bromo-1 -(2,2,2-trifluoroethyl)indoline (2.28g, 8.14mmol, 80% yield) as a yellow solid.

Ή NMR (CDC , 400MHz) δ/ppm: 7.20 (2H, m), 6.38 (1 H, d, J = 8.0Hz), 3.62 (4H, m), 3.07 (2H, t, J = 8.8Hz).

MS Method 2: RT: 2.02 min, m/z 280.9 [M+H] ⁺

[00352] Intermediate 22c: fert-Butyl 2-[1 -(2,2,2-trifluoroethyl)indolin-5-yl]acetate

[00353] Zinc powder (466mg, 7.14mmol) was suspended in dry THF (25ml_) before evacuating and back filling the flask with nitrogen. fe/f-Butyl bromoacetate (0.95ml_, 6.43mmol) was then added followed by diisobutylaluminium hydride (1 M in toluene) (0.12ml_, 0.71 mmol) which was added dropwise. The mixture was heated to 40 °C and stirred at this temperature for 2 hours. During this time the mixture had turned from a suspension to a grey solution. The solution was allowed to cool. Nitrogen was bubbled through the solution before adding 5-bromo-1 -(2,2,2-trifluoroethyl)indoline (0.55ml_, 3.57mmol), QPhos (253mg, 0.36mmol) and tris(dibenzylideneacetone)dipalladium (0) (327mg, 0.36mmol). The vessel was re-sealed, evacuated and back filled 3 times with nitrogen and heated to reflux overnight. The reaction was then cooled to room temperature. EtOAc was added to the reaction mixture which was then filtered through celite before concentrating under reduced pressure to afford a purple oil. This material was purified via column chromatography, using an eluent of 0-30% EtOAc in petroleum ether to give fe/ -butyl 2-[1 -(2,2,2-trifluoroethyl)indolin-5- yl]acetate (270mg, 0.86mmol, 24% yield) as a pale orange crystalline solid.

Ή NMR (CDCI3, 400MHz) δ/ppm: 7.04 (1 H, s), 6.99 (1 H, d, J = 7.8Hz), 6.47 (1 H, d, J = 7.8Hz), 3.60 (4H, m), 3.44 (2H, s), 3.07 (2H, t, J = 6.3Hz), 1 .46 (9H, s).

MS Method 2: RT: 2.07 min, m/z 316.1 [M+H] ⁺

[00354] Intermediate 22: 2-[1 -(2,2,2-Trifluoroethyl)indolin-5-yl]acetic acid

[00355] A stirred solution of te/ -butyl 2-[1 -(2,2,2-trifluoroethyl)indolin-5-yl]acetate (300mg, 0.95mmol) in 4M HCI in dioxane (4.76ml_, 19.03mmol) was heated at 45 °C overnight. The reaction mixture was then concentrated under reduced pressure to afford 2-[1 -(2,2,2-trifluoroethyl)indolin-5- yl]acetic acid (246mg, 0.95mmol, 100% yield) as a light brown solid.

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 12.00 (1 H, br s), 6.97 (1 H, s), 6.90 (1 H, d, J = 8.0Hz), 6.58 (1 H, d, J = 8.0Hz), 3.90 (2H, q, J = 2.5Hz), 3.50 (2H, t, J = 8.4Hz), 3.40 (2H, s), 2.96 (2H, t, J = 8.4Hz).

MS Method 2: RT: 1 .57 min, m/z 260.0 [M+H] ⁺

[00356] Intermediate 23

Scheme 12

[00357] Intermediate 23a: 5-bromo-1 -methyl-pyrrolo[2,3-b]pyridine

[00358] 5-Bromo-1 H-pyrrolo[2,3-b]pyridin (2.00g, 10.15mmol) and NaH (609mg, 15.23mmol) were stirred under N2 in DMF (40mL) for 1 hour at room temperature, lodomethane (0.95ml_, 15.23mmol) was added and left to stir for 4 hours. The reaction was quenched with 1 M NaOH (20ml_), then extracted with EtOAc (4 x 25ml_), washed with brine (4 x 25ml_) and dried over Na2S04. The compound was purified via column chromatography using an eluent of 0-75% EtOAc in petroleum ether to yield 5-bromo-1 -methyl-pyrrolo[2,3-b]pyridine (1 .00mg, 4.76mmol, 47% yield) as a yellow solid.

Ή NMR (CDCI3, 400MHz) δ/ppm: 8.36 (1 H, d, J = 2.0Hz), 8.03 (1 H, d, J = 2.0Hz), 7.21 (1 H, d, J =

3.6Hz), 6.41 (1 H, d, J = 3.6Hz), 3.89 (3H, s).

MS Method 2: RT: 1 .65 min, m/z 210.9 [M+H] ⁺ , 212.9 [M+H] ⁺

[00359] Intermediate 23b: fert-Butyl 2-(1 -methylpyrrolo[2,3-b]pyridin-5-yl)acetate

[00360] Zinc Powder (619mg, 9.48mmol) and a stirrer bar was added to a dry 3-neck flask and the flask sealed and flushed with nitrogen. The powder was then suspended in dry THF (20ml_), the suspension stirred and fe/ -butyl bromoacetate (1 .26ml_, 8.53mmol) added to the vessel.

Diisobutylaluminium hydride (1 M in toluene) (0.16ml_, 0.95mmol) was then added dropwise, at which point the suspension began to bubble. Stirring was continued for 2 hours with heating to 40 °C, until the zinc had mostly dissolved. The solution was then allowed to cool to room temperature and to the vessel was added 5-bromo-1 -methyl-pyrrolo[2,3-b]pyridine (1 .00g,

4.74mmol) and 'BuXPhos (201 mg, 0.47mmol). Nitrogen was then bubbled through the resulting stirred solution before tris(dibenzylideneacetone)dipalladium (0) (434mg, 0.47mmol) was added, the vessel re-sealed, flushed with nitrogen again, and heated to reflux overnight. The solution was filtered through celite washing with MeOH and concentrated in vacuo. The residue was taken into EtOAc (50ml_), washed with brine (2 x 50ml_) and dried over Na2S04. The organic layer was concentrated in vacuo then purified via column chromatography, using an eluent of 0 to 50% EtOAc in petroleum ether to give fe/ -butyl 2-(1 -methylpyrrolo[2,3-b]pyridin-5-yl)acetate (21 1 mg, 0.86mmol, 18% yield) as a yellow oil. Ή NMR (CDC , 400MHz) δ/ppm: 7.87 (1 H, s), 7.53 (1 H, s), 7.31 -7.24 (2H, m), 4.00 (3H, s), 3.55 (2H, s), 1 .36 (9H, s).

MS Method 2: RT: 1 .63min, m/z 247.2 [M+H] ⁺

[00361] Intermediate 23: 2-(1 -methylpyrrolo[2,3-b]pyridin-5-yl)acetic acid

[00362] A stirred solution of fe/ -butyl 2-(1 -methylpyrrolo[2,3-b]pyridin-5-yl)acetate (21 1 mg, 0.86mmol) in HCI in dioxane (4M) (0.59ml_, 17.13mmol) was heated at 45 °C for 12 hours, then concentrated in vacuo yielding 2-(1 -methylpyrrolo[2,3-b]pyridin-5-yl)acetic acid (160mg, 0.84mmol, 98% yield) as a yellow solid.

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 7.98 (1 H, d, J = 1 .0Hz), 7.61 -7.60 (1 H, m), 7.58-7.55 (1 H, m), 7.29 (1 H, dd, J = 8.7Hz, J = 1 .6Hz), 4.02 (3H, s), 3.66 (2H, s), exchangeable acid proton not seen.

[00363] Intermediate 24

Scheme 13

[00364] Intermediate 24a: 5-Bromo-3-isopropyl-1 H-indole

[00365] 3-Methylbutyraldehyde (1 .44ml_, 13.42mmol) was added to a stirred solution of

(4-bromphenyl)hydrazinhydrochloride (3.00g, 13.42mmol) in acetic acid (100ml_) at 80 °C. The resulting mixture was then stirred at 120 °C for 3 hours and monitored by LCMS. On consumption of starting materials, the reaction mixture was concentrated in vacuo, diluted with EtOAc (100ml_) and washed with H2O (100ml_) to remove residual acid. The resulting residue was purified by column chromatography using an eluent of 0-100% EtOAc in petroleum ether to afford the title compound 5- bromo-3-isopropyl-1 /-/-indole as a brown oil (2.30g, 9.67mmol, 72% yield).

Ή NMR (CDCI3, 400MHz) δ/ppm: 7.99 (1 H, br s), 7.79 (1 H, d, J = 1 .8Hz), 7.22 7.28 (2H, m), 6.98 (1 H, s), 3.1 1 -3.27 (1 H, m), 1 .36 (6H, d, J = 7.0Hz).

MS Method 2: RT: 2.02 min, m/z 239.9 [M+H] ⁺

[00366] Intermediate 24b: 5-Bromo-3-isopropyl-1 -methyl-indole [00367] NaH 60% dispersion in mineral oil (386mg, 9.66mmol) was added portion-wise to a stirred solution of 5-bromo-3-isopropyl-1 /-/-indole (2.3g, 9.66mmol) in DMF (1 1 ml_) at 0 °C under a nitrogen atmosphere. A 1 M NaOH solution chemical scrubber was attached, and iodomethane (0.60ml_, 9.66mmol) was added dropwise. The reaction was monitored by LCMS, and allowed to warm to room temperature after 3 hours of stirring. The reaction mixture was quenched with 1 M NaOH solution (50ml_), and extracted with EtOAc (2 x 30ml_). The combined organic layers were then washed with H2O (50ml_), brine (50ml_) and concentrated in vacuo to afford 5-bromo-3-isopropyl-1 - methyl-indole as brown oil (2.2g, 8.73mmol, 90% yield).

Ή NMR (CD3OD, 400MHz) δ/ppm: 7.71 -7.76 (1 H, m), 7.21 -7.26 (2H, m), 6.95-6.96 (1 H, m), 3.74 (3H, s), 3.13 (1 H, sept, J = 7.0Hz), 1 .34 (6H, d, J = 7.0Hz).

MS Method 2: RT: 2.20 min, m/z 253.8 [M+H] ⁺

[00368] Intermediate 24c: tert-Butyl 2-(3-isopropyl-1 -methyl-indol-5-yl)acetate

[00369] Zinc Powder (519mg, 7.93mmol) and a stirrer bar were added to a dry 3-neck flask and the flask sealed and flushed with nitrogen. The powder was then suspended in dry THF (20ml_), the suspension stirred and fe/ -butyl bromoacetate (1 .05ml_, 7.14mmol) added to the vessel.

Diisobutylaluminium hydride (1 M in toluene) (0.13ml_, 0.79mmol) was then added dropwise, at which point the suspension began to bubble. Stirring was continued for 2 hours with heating to 40 °C, until the zinc had mostly dissolved. The solution was then allowed to cool and to the vessel was added 5-bromo-3-isopropyl-1 -methyl-indole (1 .00g, 3.97mmol) and 'BuXPhos (168mg, 0.40mmol). Nitrogen was then bubbled through the resulting stirred solution before

tris(dibenzylideneacetone)dipalladium (0) (363mg, 0.40mmol) was added, the vessel re-sealed, flushed with nitrogen again, and heated to reflux overnight. The solution was filtered through celite washing with MeOH and concentrated in vacuo. The residue was taken into EtOAc (50ml_), washed with brine (2x50ml_) and dried over Na2S04. The organic layer was concentrated in vacuo and the residue purified via column chromatography, using an eluent of 0 to 50% EtOAc in petroleum ether to give fe/ -butyl 2-(3-isopropyl-1 -methyl-indol-5-yl)acetate (21 1 mg, 0.73mmol, 18% yield) as a yellow oil.

Ή NMR (CDCI3, 400MHz) δ/ppm: 7.78 (1 H, s), 7.67 (1 H, d, J = 1 .6Hz), 7.48-7.43 (1 H, m), 6.71 (1 H, s), 3.64 (3H, s), 3.54 (2H, s), 2.89-2.80 (1 H, m), 1 .06 (9H, s), 0.88 (6H, d, J = 6.6Hz).

MS Method 2: RT: 2.20 min, m/z 288.3 [M+H] ⁺

[00370] Intermediate 24: 2-(3-lsopropyl-1 -methyl-indol-5-yl)acetic acid

[00371] A stirred solution of fe/ -butyl 2-(3-isopropyl-1 -methyl-indol-5-yl)acetate (21 1 mg,

0.73mmol) in HCI in dioxane (4M) (0.51 mL, 14.68mmol) was heated at 45 °C for 16 hours, then concentrated in vacuo. The resulting oil was purified via column chromatography, using an eluent of 0-50% EtOAc in petroleum ether to give 2-(3-isopropyl-1 -methyl-indol-5-yl)acetic acid (50mg, 0.22mmol, 29% yield).

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 7.45 (1 H, s), 7.16 (1 H, d, J = 8.5Hz), 7.05 (1 H, dd, J = 8.5Hz, 1 .6Hz), 6.72 (1 H, s), 3.69 (2H, s), 3.64 (3H, s), 3.15-3.05 (1 H, m), 1 .27 (3H, s), 1 .25 (3H, s), exchangeable acid proton not seen.

MS Method 2: RT: 1 .67 min, m/z 232.2 [M+H] ⁺ [00372] Intermediate 25

25a 25

Scheme 14

[00373] Intermediate 25a: fert-Butyl 2-(6-methoxy-3-pyridyl)acetate

[00374] LiHMDS 1 M in toluene (15.96ml_, 15.96mmol) was added to a stirred solution of 5-bromo- 2-methoxy-pyridine (0.69ml_, 5.32mmol), fe/f-butyl acetate (1 .08ml_, 7.98mmol) and chloro[2-(di- fe/?-butylphosphino)-2',4',6'-triisopropyl-1 ,1 '-biphenyl][2-(2-aminoethyl)phenyl)]palladium(ll) (36mg, 0.05mmol) in toluene (3ml_) under nitrogen. The reaction mixture was allowed to stir for 12 hours at 0 °C. Sat. aq. NhUCI (6ml_) was added, then the mixture was extracted three times with EtOAc. The combined organic fractions were dried over Na2S04, and the solvents were then removed in vacuo. The residue was purified via column chromatography using an eluent of 10 to 20% EtOAc in heptane to give fe/f-butyl 2-(6-methoxy-3-pyridyl)acetate (1 15mg, 0.51 mmol, 10% yield) as a colourless oil.

Ή NMR (CDC , 400MHz) δ/ppm: 7.96 (1 H, d, J = 2.3Hz), 7.47 (1 H, dd, J = 8.5Hz, 2.3Hz), 6.66 (1 H, d, J = 8.5Hz), 3.86 (3H, s), 3.37 (2H, s), 1 .36 (9H, s).

MS Method 2: RT: 1 .67 min, m/z 224.1 [M+H] ⁺ .

[00375] Intermediate 25: 2-(6-Methoxy-3-pyridyl)acetic

[00376] A stirred solution of fe f-butyl 2-(6-methoxy-3-pyridyl)acetate (1 12mg, 0.50mmol) in 4M HCI in dioxane (0.35ml_, 10.03mmol) was heated at 45 °C for 16 hours, then concentrated in vacuo yielding 2-(6-methoxy-3-pyridyl)acetic acid (80mg, 0.48mmol, 95% yield).

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 8.03 (1 H, d, J = 2.6Hz), 7.62 (1 H, dd, J = 8.5Hz, 2.6Hz), 6.80 (1 H, d, J = 8.5Hz), 3.84 (3H, s), 3.54 (2H, s) exchangeable acid proton not seen.

MS Method 2: RT: 1 .68 min, m/z 168.0 [M+H] ⁺ .

[00377] Intermediate 26

[00378] In a similar manner to the synthesis of Intermediate 25, Scheme 14, Intermediate 26 may be synthesised by varying the aryl chloride used.

[00379] Intermediate 26a: fert-Butyl 2-[2-(trifluoromethyl)-4-pyridyl]acetate

[00380] LiHMDS 1 M in toluene (8.26mL, 8.26mmol) was added to a stirred solution of 4-chloro-2- trifluoromethylpyridine (500mg, 2.75mmol), fe f-butyl acetate (0.56mL, 4.13mmol) and fBuXPhos Pd G1 (19mg, 0.03mmol) in toluene (3mL) in a 3 neck flask evacuated/backfilled with N2 held at 0 °C. The reaction mixture was allowed to stir for 16 hours at 0 °C. Sat. aq. NH4CI (6mL) was then added and the reaction mixture was extracted in EtOAc (3 x 15mL). The combined organic fractions were dried over Na2S04, solvents removed under vacuum and resulting residue purified via column chromatography using an eluent of 10-20% EtOAc in heptane to yield fe/f-butyl 2-[2- (trifluoromethyl)-4-pyridyl]acetate (324mg, 1 .24mmol, 45% yield) as a yellow oil.

Ή NMR (CDC , 400MHz) δ/ppm: 8.60 (1 H, d, J = 4.8Hz), 7.57-7.55 (1 H, m), 7.36-7.33 (1 H, m),

3.56 (2H, s), 1 .38 (9H, s).

MS Method 2: RT: 1 .82 min, m/z 262.2 [M+H] ⁺ , 206.2 [M-'Bu] ⁺

[00381] Intermediate 26: 2-[2-(Trifluoromethyl)-4-pyridyl]acetic

[00382] te/ -Butyl 2-[2-(trifluoromethyl)-4-pyridyl]acetate (298mg, 1 .14 mmol) was added to a stirred solution of 4 M HCI in dioxane (10ml_) and heated at 45 °C for 12 hours. The solvents were removed under vacuum to yield 2-[2-(trifluoromethyl)-4-pyridyl]acetic (155mg, 0.76mmol, 66% yield) as a light yellow solid.

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 12.70 (1 H, s), 8.70 (1 H, d, J = 4.8Hz), 7.85 (1 H, s), 7.65-7.63 (1 H, m), 3.84 (2H, s).

MS Method 2: RT: 1 .20 min, m/z 206.0 [M+H] ⁺

[00383] Intermediate 27

27a 27

Scheme 15

[00384] Intermediate 27a: 2-[6-(Trifluoromethyl)-3-pyridyl]acetonitrile

[00385] Potassium carbonate (2.50g, 18.17mmol) was added to a stirred solution of 5-fluoro-2- (trifluoromethyl)pyridine (0.73ml_, 6.06mmol), benzyl(triethyl)ammonium chloride (138mg,

0.61 mmol) and ethyl cyanoacetate (0.71 mL, 6.66mmol) in DMSO (6ml_). The solution was heated to 90 °C overnight and was monitored by LCMS. Upon completion the reaction was allowed to warm to room temperature. The reaction mixture was diluted with EtOAc (30ml_) and poured into 6M HCI solution (20ml_). The layers were separated and the aqueous extracted with EtOAc (2 x 20ml_). The combined organic layers were washed with brine (5 x 15ml_), dried over Na2S04, filtered and concentrated in vacuo to yield ethyl 2-cyano-2-[6-(trifluoromethyl)-3-pyridyl]acetate as a yellow oil, MS Method 2: RT: 1 .61 min, m/z 259.0 [M+H] ⁺ . The crude product was then taken onto the next step without purification. Ethyl 2-cyano-2-[6-(trifluoromethyl)-3-pyridyl]acetate was dissolved in DMSO (1 OmL) and brine (30ml_) and was heated at 1 10 °C overnight. The mixture was allowed to cool to room temperature, diluted with H2O (100ml_) and extracted with EtOAc (2x30ml_). The combined organic layers were washed with brine (3 x 50ml_), dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by column chromatography using an eluent of 10 to 70% EtOAc in heptane to give 2-[6-(trifluoromethyl)-3-pyridyl]acetonitrile as a yellow oil (600mg, 3.22mmol, 53% over two steps). Ή NMR (DMSO-d6, 400 MHz) δ/ppm: 8.77 (1 H, m), 8.09-8.1 1 (1 H, m), 7.97 (1 H, d, J = 8.1 Hz), 4.26 (2H, s).

MS Method 2: RT: 1 .35 min, m/z 186.9 [M+H] ⁺

[00386] Intermediate 27: 2-[6-(Trifluoromethyl)-3-pyridyl]acetic acid

[00387] 2-[6-(Trifluoromethyl)-3-pyridyl]acetonitrile (600mg, 3.22mmol) was suspended in 1 ,4- dioxane (4ml_) and aqueous hydrogen chloride (6 M, 1 .1 mL, 6.44mmol). The solution was exposed to microwave irradiation at 130 °C for 90 minutes. The solvents were removed in vacuo. The residue was purified by reverse phase chromatography eluting with 5-30% MeCN (0.1 % formic acid) in H2O (0.1 % formic acid) to yield 2-[6-(trifluoromethyl)-3-pyridyl]acetic acid as a colourless solid (170mg, 0.83mmol, 26% yield).

Ή NMR (CDCI3, 400MHz) δ/ppm: 8.69 (1 H, s), 7.87 (1 H, dd, J = 7.9Hz, 1 .6Hz), 7.70 (1 H, d, J =

7.9Hz), 3.80 (2H, s), 1 .56 (1 H, s).

MS Method 2: RT: 1 .22 min, m/z 205.9 [M+H] ⁺

[00388] Intermediate 28

Scheme 16

[00389] Intermediate 28a: Ethyl 2-(1 ,3-benzothiazol-2-yl)acetate

[00390] 2-Aminothiophenol (1 .00g, 7.99mmol) and ethyl cyanoacetate (3.40ml_, 31 .95mmol) were heated at 120 °C overnight. After cooling to room temperature the mixture was subjected directly to column chromatography eluting with 0 to 20% EtOAc in heptane) to give ethyl 2-(1 ,3-benzothiazol- 2-yl)acetate (704mg, 3.18mmol, 40% yield) as a bright orange oil.

Ή NMR (CDCI3, 400MHz) δ/ppm: 8.05 (1 H, d, J = 8.4Hz), 7.91 (1 H, d, J = 8.0Hz), 7.53 (1 H, m), 7.43 (1 H, m), 4.28 (2H, q, J = 7.2Hz), 4.23 (2H, s), 1 .33 (3H, t, J = 7.2Hz).

MS Method 2: RT: 1 .61 min, m/z 222.1 [M+H] ⁺

[00391] Intermediate 28: Sodium 2-(1 ,3-benzothiazol-2-yl)acetate

[00392] Ethyl 2-(1 ,3-benzothiazol-2-yl)acetate (627μΙ_, 3.07mmol) was dissolved in EtOH (8ml_) and water (58μΙ_, 3.23mmol) and heated to 60 °C. A solution of sodium fe/ -butoxide (295mg, 3.07mmol) in EtOH (2ml_) was then added dropwise and the reaction was stirred at 60 °C overnight. The EtOH was removed in vacuo and the resulting residue triturated with Εί∑0 and dried in the vac oven to yield sodium 2-(1 ,3-benzothiazol-2-yl)acetate (412mg, 1 .91 mmol, 62% yield) as a yellow powder.

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 7.96 (1 H, d, J = 7.4Hz), 7.84 (1 H, d, J = 7.4Hz), 7.39 (1 H, m), 7.32 (1 H, m), 3.66 (2H, s), exchangeable carboxylic acid proton not seen.

MS Method 2: RT: 1 .24 min, m/z 194.0 [M+H] ⁺

[00393] Intermediate 29

Scheme 17

[00394] Intermediate 29a: diethyl 2-[4-nitro-3-(trifluoromethyl)phenyl]propanedioate

[00395] A solution of diethyl malonate (1 .31 ml_, 8.61 mmol) and caesium carbonate (5.14g, 15.78mmol) in DMF (20ml_) was heated to 70 °C. 5-Fluoro-2-nitrobenzotrifluoride (1 .OOmL, 7.17mmol) was then added and the mixture turned from a cloudy suspension to a dark purple solution. The mixture was then cooled to room temperature. The basic mixture was brought to neutral pH using a few drops of acetic acid. The mixture was diluted with EtOAc before washing twice with water. The combined organic layers were washed with brine before being dried over Na2S04, filtered and concentrated under reduced pressure to afford an orange oil. The crude material was purified via column chromatography using an eluent of 5 to 20% EtOAc in heptane to give diethyl 2-[4-nitro-3-(trifluoromethyl)phenyl]propanedioate (1 .36g, 3.89mmol, 54% yield) afforded as a pale yellow oil.

Ή NMR (CDC , 400MHz) δ/ppm: 7.91 (2H, m), 7.84 (1 H, dd, J = 8.4Hz, 1 .6Hz), 4.76 (1 H, s), 4.26 (4H, m), 1 .29, (6H, m).

MS Method 2: RT: 1 .89 min, m/z 350.0 [M+H] ⁺

[00396] Intermediate 29b: diethyl 2-[4-amino-3-(trifluoromethyl)phenyl]propanedioate

[00397] To a degassed solution of diethyl 2-[4-nitro-3-(trifluoromethyl)phenyl]propanedioate (1 .36g, 3.89mmol) in EtOAc (40ml_) (evacuated and back filled three times with nitrogen) was added palladium on carbon, 10 wt. % loading (76mg, 0.39mmol). The flask was then evacuated and back filled with hydrogen three times. The reaction mixture was left to stir at room temperature overnight.The reaction mixture was then degassed and back filled three times with N2 before filtering through celite. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using an eluent of 5 to 50% EtOAc in petroleum ether to give diethyl 2-[4-amino-3-(trifluoromethyl)phenyl]propanedioate (836mg, 2.62mmol, 67% yield) as a yellow oil.

Ή NMR (CDCI3, 400MHz) δ/ppm: 7.45 (1 H, d, J = 1 .6Hz), 7.38 (1 H, dd, J = 8.4Hz, 2.0Hz), 6.75 (1 H, d, J = 2.1 Hz), 4.52 (1 H, s), 4.27 (4H, m), 3.91 (2H, br s), 1 .29, (6H, m).

MS Method 2: RT: 1 .74 min, m/z 320.2 [M+H] ⁺ [00398] Intermediate 29c: diethyl 2-[4-(dimethylamino)-3- (trifluoromethyl)phenyl]propanedioate

[00399] To a solution of diethyl 2-[4-amino-3-(trifluoromethyl)phenyl]propanedioate (670mg, 2.10mmol) in acetic acid (20ml_) was added paraformaldehyde (504mg, 10.50mmol) and sodium tnacetoxyborohydride (1 .33g, 6.30mmol). The mixture was stirred at room temperature for 72 hours. LCMS suggested starting material still present. Paraformaldehyde (504mg, 10.5mmol) and sodium triacetoxyborohydride (1 .33g, 6.30mmol) were added to the reaction mixture and left to stir overnight. The reaction mixture was diluted with water and sat. aq. NaHC03 added to neutralise the solution before extracting twice with EtOAc. The combined organic layers were washed with brine, dried over Na2S04 and passed through a hydrophobic frit. Solvent was removed under reduced pressure. The residue was purified by column chromatography using an eluent of 20 to 80% EtOAc in heptane to give diethyl 2-[4-(dimethylamino)-3-(trifluoromethyl)phenyl]propanedioate (508mg, 1 .46mmol, 69% yield) as a yellow/orange oil.

Ή NMR (CDC , 400MHz) δ/ppm: 7.63 (1 H, m), 7.58 (1 H, m), 7.33 (1 H, m), 4.61 (1 H, s), 4.26 (4H, m), 2.77 (6H, s), 1 .28 (6H, t, J = 7.2Hz).

MS Method 2: RT: 2.85 min, m/z 348.1 [M+H] ⁺

[00400] Intermediate 29: 2-[4-(dimethylamino)-3-(trifluoromethyl)phenyl]acetic acid hydrochloride

[00401] A solution of diethyl 2-[4-(dimethylamino)-3-(trifluoromethyl)phenyl]propanedioate (508mg, 1 .46mmol) in water (2ml_) and 6M HCI (3.1 ml_, 1 .46mmol) was heated at 90 °C overnight. The reaction was then concentrated under reduced pressure to afford 2-[4-(dimethylamino)-3- (trifluoromethyl)phenyl]acetic acid hydrochloride (414mg, 1 .46mmol, 100% yield) as a pale yellow solid.

Ή NMR (CDCI3, 400MHz) δ/ppm: 8.05 (1 H, d, J = 8.8Hz), 7.86 (2H, m), 3.84 (2H, m), 3.33 (6H, s), exchangeable carboxylic acid proton not seen.

MS Method 2: RT: 1 .80 min, m/z 248.1 [M+H] ⁺

[00402] Intermediate 30

[00403] In a similar manner to the synthesis of Intermediate 29, Scheme 17, Intermediate 30 may be synthesised, by varying the aryl fluoride used.

[00404] Intermediate 30a: Diethyl 2-(3-methoxy-4-nitro-phenyl)propanedioate

[00405] A solution of diethyl malonate (1 .60ml_, 10.52mmol) and caesium carbonate (6.28g, 19.28mmol) in DMF (20ml_) was heated to 70 °C. 5-Fluoro-2-nitroanisole (1 .OOmL, 8.77mmol) was then added and the mixture turned from a cloudy suspension to a dark purple solution. The mixture was cooled to room temperature. The basic mixture was brought to neutral pH using a few drops of acetic acid. The mixture was diluted with EtOAc before washing twice with water. The combined organics were washed with brine before being dried over Na2S04, filtered and concentrated under reduced pressure to afford an orange oil. The crude material was purified via column

chromatography using an eluent of 5-20% EtOAc in heptane to give diethyl 2-(3-methoxy-4-nitro- phenyl)propanedioate (1 .81 g, 5.81 mmol, 66% yield) as a pale yellow oil.

Ή NMR (CDC , 400MHz) δ/ppm: 7.84 (1 H, d, J = 8.4Hz), 7.23 (1 H, d, J = 1 .6Hz), 7.06 (1 H, dd, J = 8.4Hz, 1 .6Hz), 4.67 (1 H, s), 4.20 (4H, m), 4.04 (3H, s), 1 .27 (6H, m).

MS Method 2: RT: 1 .89 min, m/z 350.0 [M+H] ⁺

[00406] Intermediate 30b: 2-(4-Amino-3-methoxy-phenyl)propanedioate

[00407] To a degassed solution of diethyl 2-(3-methoxy-4-nitro-phenyl)propanedioate (1 .81 g, 5.81 mmol) in EtOAc (40ml_) (evacuated and back filled three times with nitrogen) was added palladium on carbon, 10 wt. % loading (1 13mg, 0.58mmol). The flask was then evacuated and back filled with hydrogen three times. The reaction mixture was left to stir at room temperature overnight. The reaction mixture was then degassed and back filled three times with N2 before filtering through celite. The filtrate was concentrated under reduced pressure to afford diethyl 2-(4-amino-3-methoxy- phenyl)propanedioate (1 .35g, 4.80mmol, 82% yield) as a yellow oil.

Ή NMR (CDCI3, 400MHz) δ/ppm: 6.91 (1 H, d, J = 2.0Hz), 6.81 (1 H, dd, J = 8.0Hz, 2.0Hz), 6.71 (1 H, d, J = 4.8Hz), 4.51 (1 H, s), 4.25 (4H, m), 3.88 (3H, s), 3.60 (2H, br s), 1 .31 (6H, m).

MS Method 2: RT: 1 .39 min, m/z 282.2 [M+H] ⁺

[00408] Intermediate 30c: Diethyl 2-[4-(dimethylamino)-3-methoxy-phenyl]propanedioate

[00409] To a solution of paraformaldehyde (512mg, 10.67mmol) in acetic acid (20ml_) was added diethyl 2-(4-amino-3-methoxy-phenyl)propanedioate (600mg, 2.13mmol) and sodium

triacetoxyborohydride (1 .36g, 6.40mmol). The mixture was stirred at room temperature overnight. LCMS indicated about 34% monomethylated material with majority starting material remaining. Further paraformaldehyde was added (2eq.) and the reaction mixture left to stir at room

temperature overnight. The mixture was diluted with water and sat. aq. NaHCC added to neutralise the solution before extracting twice with EtOAc. Combined organics were washed with brine, dried over Na2S04 and passed through a hydrophobic frit. Solvent was removed under reduced pressure. The residue was purified via column chromatography using an eluent of 10-80% EtOAc in heptane to afford diethyl 2-[4-(dimethylamino)-3-methoxy-phenyl]propanedioate (132mg, 0.43mmol, 20% yield) as a pale yellow oil.

Ή NMR (CDCI3, 400MHz) δ/ppm: 6.96 (1 H, s), 6.92 (2H, s), 4.57 (1 H, s), 4.22 (4H, m), 3.91 (3H, s), 2.80 (6H, s), 1 .25 (6H, m).

MS Method 2: RT: 1 .18min, m/z 310.2 [M+H] ⁺

[00410] Intermediate 30: 2-[4-(Dimethylamino)-3-methoxy-phenyl]acetic acid

[00411] A solution of diethyl 2-[4-(dimethylamino)-3-methoxy-phenyl]propanedioate (132mg, 0.43mmol) in water (2ml_) and hydrogen chloride (3.1 mL, 0.43mmol) (6N solution) was heated at 90 °C overnight. The reaction was allowed to cool to room temperature and neutralised with 1 M NaOH before extracting with 'BuOH. The solvent was removed under reduced pressure to afford 2- [4-(dimethylamino)-3-methoxy-phenyl]acetic acid (55mg, 0.26mmol, 61 % yield) as a light brown. Ή NMR (CDC , 400MHz) δ/ppm: 8.10 (1 H, m), 7.23 (1 H, m), 7.03 (1 H, m), 6.93 (1 H, m), 4.01 (3H, s), 3.70 (2H, s), 3.27 (6H, s).

MS Method 2: RT: 0.59 min, m/z 210.0 [M+H] ⁺

[00412] Intermediate 31

Scheme 18

[00413] Intermediate 31a: Diethyl 2-(6-chloropyridazin-3-yl)propanedioate

[00414] Diethyl malonate (1 .08ml_, 7.05mmol) added dropwise at 0 °C to a suspension of NaH (60% dispersion in mineral oil) (375mg, 9.4mmol) in dioxane (25ml_) and the mixture stirred at 0 °C for 1 hour. The reaction was allowed to warm to room temperature and 3,6-dichloropyridazine (700mg, 4.70mmol) added portionwise. The reaction was then stirred at reflux for 17 hours. The solvent was removed under vacuum and the residue dissolved in EtOAc (50ml_). The organic solution was washed with sat. aq. NaHC03 followed by sat. aq. NhUCI. The organic layer was dried over Na2S04, filtered and evaporated to an orange oil. The orange oil was purified by column chromatography using an eluent of 20% EtOAc in petroleum ether to give diethyl 2-(6- chloropyridazin-3-yl)propanedioate as a yellow oil (610 mg, 2.24mmol, 49% yield).

Ή (CDCI3, 400MHz) δ/ppm: 7.76 (1 H, d, J = 8.6Hz), 7.75 (1 H, d, J = 9.0Hz), 5.19 (1 H, s), 4.27-4.12 (4H, m), 1 .28-1 .16 (6H, t, J = 7.4).

MS Method 2: RT: 1 .51 min, m/z 273.9 [M+H] ⁺

[00415] Intermediate 31 : 2-(6-Chloropyridazin-3-yl)acetic acid

[00416] A solution of diethyl 2-(6-chloropyridazin-3-yl)propanedioate (610mg, 2.24mmol) and LiOH (107mg, 4.47mmol) in MeOH:water (3:1 , 20ml_) was stirred at room temperature for 67 hours. MeOH was removed from the reaction via rotary evaporation and the resulting residue was reconstituted in H2O (30ml_). The aqueous mixture was washed with EtOAc (3 x 10ml_) and then the aqueous layer was concentrated under vacuum to give a white solid 2-(6-chloropyridazin-3-yl)acetic acid as a white solid (396mg, 2.22 mmol, 99% yield). The material was used in the next step without further purification.

Ή NMR (DMSO, 400MHz) δ/ppm: 7.70 (2H, q, J = 8.93Hz), 3.56 (2H, s), exchangeable carboxylic acid proton not seen.

MS Method 2: RT: 0.71 min, m/z 172.9 [M+H] ⁺

[00417] Intermediate 32 [00418] In a similar manner to the synthesis of Intermediate 31 , Scheme 18, Intermediate 32 may be synthesised, by varying the aryl chloride used.

[00419] Intermediate 32a: Diethyl 2-[6-(trifluoromethyl)pyridazin-3-yl]propanedioate

[00420] Diethyl malonate (0.63ml_, 4.1 1 mmol) added dropwise at 0 °C to a suspension of NaH (60% dispersion in mineral oil) (219mg, 5.48mmol) in dioxane (20ml_) and the mixture stirred at 0 °C for 1 hour. The reaction was allowed to warm to room temperature and 3-chloro-6- (trifluormethyl)pyridazine (500mg, 2.74mmol) added portionwise. The reaction was then stirred at reflux for 18 hours . The solvent was then removed under vacuum and the residue dissolved in EtOAc (50ml_). The organic solution was washed with sat. aq. NaHC03 followed by sat. NhUCI. The organic layer was dried over Na2S04, filtered and evaporated to give a dark red oil. The crude material was purified by column chromatography using an eluent of 20% EtOAc in petroleum ether to give a yellow oil of diethyl 2-[6-(trifluoromethyl)pyridazin-3-yl]propanedioate (445mg, 1 .45mmol, 53% yield).

Ή NMR (CDC , 400MHz) δ/ppm: 7.99 (1 H, d, J = 8.8Hz), 7.79 (1 H, d, J = 8.8Hz), 5.33 (1 H, s), 4.29 - 4.16 (4H, m), 1 .28 - 1 .14 (6H, m).

MS Method 2: RT: 1 .66 min, m/z 307.0 [M+H] ⁺

[00421] Intermediate 32: 2-[6-(trifluoromethyl)pyridazin-3-yl]acetic acid

[00422] A solution of diethyl 2-[6-(trifluoromethyl)pyridazin-3-yl]propanedioate (445mg, 1 .45mmol) and LiOH (107mg, 4.47mmol) in MeOH:Water (3:1 , 20ml_) was stirred at room temperature for 21 hours. MeOH was then removed from the reaction via rotary evaporation and the resulting residue was reconstituted in H2O (30ml_). The aqueous mixture was washed with Εί∑0 (3 x 20ml_) and then the aqueous layer was concentrated under vacuum to give 2-[6-(trifluoromethyl)pyridazin-3-yl]acetic acid as a white solid (460mg, 130% - excess mass due to lithium salts) which was used in the next step without further purification.

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 8.05 (1 H, d, J = 8.9Hz), 7.86 (1 H, d, J = 8.9Hz), 3.66 (2H, s), exchangeable carboxylic acid proton not seen.

MS Method 2: RT: 1 .02 min, m/z 207.0 [M+H] ⁺

[00423] Intermediate 33

Scheme 19

[00424] Intermediate 33a: Ethyl (2S)-2-amino-2-phenyl-acetate

[00425] A stirred solution of (2S)-2-amino-2-phenyl-acetic acid (5.00g, 33.08mmol) in EtOH (150ml_) and H2SO4 (2.23ml_, 39.69mmol) was heated at 50 °C overnight. The solution was concentrated in vacuo and the residue was poured into EtOAc (50ml_) and NaHC03 (50ml_). The product was extracted twice more with EtOAc (2 x 50ml_), organic fractions combined, dried over Na2S04 and concentrated in vacuo to yield ethyl (2S)-2-amino-2-phenyl-acetate (2.34g, 13.08mmol, 39% yield)

Ή NMR (CDCI3, 400MHz) δ/ppm: 7.33-7.18 (5H, m), 4.52 (1 H, s), 4.17-4.00 (2H, m), 1 .78, (2H, br s), 1 .14 (3H, t, J = 7.0Hz).

[00426] Intermediate 33b: ethyl (2S)-2-(benzyloxycarbonylamino)-2-phenyl-acetate

[00427] Benzyl (2,5-dioxopyrrolidin-1 -yl) carbonate (0.70g, 2.79mmol) in MeCN (20ml_) was added dropwise to a stirred solution of ethyl (2S)-2-amino-2-phenyl-acetate (0.46ml_, 2.79mmol) in MeCN (20ml_) . The reaction mixture was stirred at room temperature for 2 hours. The solution was concentrated in vacuo, then diluted with EtOAc (20ml_) and sat. aq. NaHC03 (20ml_). Product was extracted from the aqueous phase with EtOAc (2 x 20ml_) and organic fractions were combined, washed with brine (30ml_), dried over Na2S04 and solvents removed in vacuo to give ethyl (2S)-2- (benzyloxycarbonylamino)-2-phenyl-acetate (810mg, 2.58mmol, 93% yield).

Ή NMR (CDCI3, 400MHz) δ/ppm: 7.32-7.20 (1 OH, m), 5.77 (1 H, d, J = 6.7Hz), 5.28 (1 H, d, J = 7.4Hz), 5.02 (2H, dd, J = 12.3Hz, 22.0Hz), 4.21 -4.01 (2H, m), 1 .13 (3H, t, J = 7.0Hz).

MS Method 2: RT: 2.50min, m/z 314.1 [M+H] ⁺

[00428] Intermediate 33: (2S)-2-(benzyloxycarbonylamino)-2-phenyl-acetic acid

[00429] A solution of ethyl (2S)-2-(benzyloxycarbonylamino)-2-phenyl-acetate (250mg, 0.80mmol) and potassium trimethylsilanolate (204mg, 1 .60mmol) in THF (25ml_) was stirred for 16 hours at room temperature. The reaction mixture was then filtered and the organic solute concentrated in vacuo to give (2S)-2-(benzyloxycarbonylamino)-2-phenyl-acetic acid (215mg, 0.75mmol, 94% yield) as a white solid.

Ή NMR (CDC , 400MHz) δ/ppm: 7.25-7.09 (10H, m), 4.93 (1 H, s), 3.94 (1 H, s), 1 .94 (2H, d, J = 2.0Hz), exchangeable carboxylic acid proton not seen.

MS Method 2: RT: 1 .91 min, m/z 284.0 [M-H] ^"

[00430] Intermediate 34

[00431] In a similar manner to the synthesis of Intermediate 33, Scheme 19, Intermediate 34 may be synthesised, by varying the amino acid used.

[00432] Intermediate 34a: Ethyl (2S)-2-amino-3-phenyl-propanoate

[00433] A stirred solution of (2S)-2-amino-3-phenyl-propanoic acid (5.00g, 30.27mmol) in EtOH (150ml_) and sulfuric acid (2.04ml_, 36.32mmol) was heated at 50 °C overnight. The solution was concentrated in vacuo and the residue was poured into EtOAc (50ml_) and NaHCC (50ml_). The product was extracted twice more with EtOAc (2 x 50ml_), organic fractions combined, dried over Na2S04 and concentrated in vacuo to yield ethyl (2S)-2-amino-3-phenyl-propanoate (1 .76g, 9.13mmol, 30% yield).

Ή NMR (CDCI3, 400MHz) δ/ppm: 7.26-7.1 1 (5H, m), 4.09 (2H, q, J = 7.2Hz), 3.64 (1 H, dd, J = 8.0Hz, 5.4Hz), 3.01 (1 H, dd, J = 5.4Hz, 13.8Hz), 2.80 (1 H, dd, J = 8.0Hz, 13.8Hz), 1 .50 (2H, br s), 1 .17 (3H, t, J = 7.2Hz).

[00434] Intermediate 34b: Ethyl (2S)-2-(benzyloxycarbonylamino)-3-phenyl-propanoate

[00435] Benzyl (2,5-dioxopyrrolidin-1 -yl) carbonate (0.64g, 2.59mmol) in MeCN (20ml_) was added dropwise to a stirred solution of ethyl (2S)-2-amino-3-phenyl-propanoate (0.46ml_, 2.59mmol) in MeCN (20ml_). The reaction mixture was stirred at room temperature for 2 hours. The solution was concentrated in vacuo, then diluted with EtOAc (20ml_) and NaHC03 (20ml_). Product was extracted from the aqueous phase with EtOAc (2 x 20ml_) and organic fractions were combined, washed with brine (30ml_), dried over Na2S04 and solvents removed in vacuo to yield ethyl (2S)-2- (benzyloxycarbonylamino)-3-phenyl-propanoate (745mg, 2.27mmol, 88% yield).

Ή NMR (CDCI3, 400MHz) δ/ppm: 7.31 -7.01 (10H, m), 5.15 (1 H, d, J = 7.4Hz), 5.02 (2H, s), 4.56 (1 H, dd, J = 6.7Hz, 14.1 Hz), 4.09 (2H, dd, J = 14.1 Hz, 6.7Hz), 3.03 (2H, t, J = 5.9Hz), 1 .15 (3H, t, J = 7.4Hz).

MS Method 2: RT: 2.57min, m/z 328.1 [M+H] ⁺

[00436] Intermediate 34: (2S)-2-(Benzyloxycarbonylamino)-3-phenyl-propanoic acid

[00437] A solution of ethyl (2S)-2-(benzyloxycarbonylamino)-3-phenyl-propanoate (250mg, 0.76mmol) and potassium trimethylsilanolate (195mg, 1 .53mmol) in THF (25ml_) was stirred for 16 hours at room temperature. The reaction mixture was then filtered and the organic solute concentrated in vacuo.io give (2S)-2-(benzyloxycarbonylamino)-3-phenyl-propanoic acid (1 15mg, 0.38mmol, 50% yield) which was used in the next step without further purification.

MS Method 2: RT: 2.07min, m/z 300.1 [M+H] ⁺

[00438] Intermediate 35

[00439] Intermediate 35: 6-(Trifluoromethyl)pyridazin-3-amine

[00440] A solution of 3-chloro-6-(trifluoromethyl)pyridazine (250mg, 1 .37mmol) and ammonium hydroxide (7.0ml_, 1 .37mmol) in THF (3mL) was heated in the microwave at 100 °C for 1 hour. LCMS showed conversion to product. The solvent was removed in vacuo and then extracted twice with DCM. The combined organic layers were dried over anhydrous Na2S04, filtered and the solvent removed in vacuo to afford 6-(trifluoromethyl)pyridazin-3-amine (163mg, 0.99mmol, 73% yield). Ή NMR (DMSO-d6, 400MHz) δ/ppm: 7.53 (1 H, d, J = 9.4Hz), 6.85 (1 H, d, J = 9.4Hz), 5.21 (2H, bs).

MS Method 2: RT: 1 .82 min, m/z 163.7[M+H] ⁺ , 327.0 [2M+H] ⁺

[00441] Intermediate 36

36a 36

Scheme 20

[00442] Intermediate 36a: diethyl 2-[4-cyano-3-(trifluoromethyl)phenyl]propanedioate

[00443] A solution of diethyl malonate (4.03ml_, 26.44mmol) and caesium carbonate (18.95g, 58.17mmol) in DMF (50ml_) was heated to 70 °C under nitrogen for 30 minutes. 2-cyano-5- fluorobenzotrifluoride (5.00g, 26.44mmol) was then added. The reaction mixture was then stirred at 70 °C for 2 hours. The mixture was cooled to room temperature, diluted with EtOAc and poured into water. The aqueous layer was brought to a neutral pH with concentrated HCI and the crude product extracted into EtOAc (3x100ml_). The combined organic layers were then dried over Na2S04 and concentrated to give diethyl 2-[4-cyano-3-(trifluoromethyl)phenyl]propanedioate (7.39g, 22.44mmol, 85% yield) as a yellow oil.

MS Method 2: RT: 2.56 min, m/z 330.1 [M+H] ⁺ [00444] Intermediate 36: 2-[4-cyano-3-(trifluoromethyl)phenyl]acetic acid

[00445] To a solution of diethyl 2-[4-cyano-3-(trifluoromethyl)phenyl]propanedioate (2.00g, 6.07mmol) in MeOH (20ml_) was added 5M NaOH (5.00ml_, 25.00mmol) and the reaction mixture heated at 50 °C for 2 hours. The organic solvent was then removed under vacuum and the aqueous residue poured into water (100ml_) and this was extracted with EtOAc (3 x 50ml_) The combined organic layers were then dried over Na2S04 and concentrated in vacuo to give 2-[4-cyano-3- (trifluoromethyl)phenyl]acetic acid (947mg, 4.13mmol, 68% yield) as a clear oil.

MS Method 2: RT: 1 .64 min, m/z 228.0 [M-H] ^"

[00446] Intermediate 37:

37a 37

Scheme 21

[00447] Intermediate 37a: benzyl 2-(3-oxo-1 ,4-benzoxazin-4-yl)acetate

[00448] A solution of 2/-/-1 ,4-Benzoxazin-3(4/-/)-one (150mg, 1 .01 mmol), benzyl bromoacetate (0.19ml_, 1 .21 mmol) and potassium carbonate (416mg, 3.02mmol) in MeCN (5ml_) was heated to 60 °C and left to stir at reflux for 36 hours. The reaction mixture was quenched with water (20ml_) and extracted using DCM (3 x 20ml_). The combined organic layers were dried over Na2S04 and reduced in vacuo. This residue was purified by flash column chromatography using an eluent of in 50% EtOAc in heptane to give benzyl 2-(3-oxo-1 ,4-benzoxazin-4-yl)acetate (270mg, 0.91 mmol, 90% yield) as a yellow oil.

MS Method 3: RT: 3.95 min, m/z 298.1 [M+H] ⁺

[00449] Intermediate 37: 2-(3-oxo-1 ,4-benzoxazin-4-yl)acetic acid

[00450] A flask containing benzyl 2-(3-oxo-1 ,4-benzoxazin-4-yl)acetate (270mg, 0.91 mmol) in EtOAc (5ml_) was degassed with nitrogen before the addition of palladium, 10 wt. % on carbon powder, wet support (19mg, 0.18mmol). The reaction mixture was hydrogenated overnight while heating at 50 °C. The reaction mixture was left to cool to room temperature before being degassed with nitrogen and filtered through celite. The filter cake was washed with EtOAc (200ml_) and MeOH (50ml_). Solvent was removed in vacuo to give 2-(3-oxo-1 ,4-benzoxazin-4-yl)acetic acid (180mg, 0.86mmol, 95% yield) as a grey solid which was used in the next step without further purification. Ή NMR (CDCIs, 400MHz) δ/ppm: 7.07-7.03 (3H, m), 6.86-6.81 (1 H, m), 4.74 (2H, s), 4.71 (2H, s), exchangeable proton not seen.

MS Method 3: RT: 3.00 min, m/z 206 [M-H] ^"

[00451] Intermediate 38:

Scheme 22

[00452] Intermediate 38a: ethyl 2-[4-(trifluoromethyl)pyrimidin-2-yl]acetate

[00453] To a solution of sodium hydride (1 .18g, 29.58mmol) in DMF (6ml_) was added diethyl malonate (4.35ml_, 28.69mmol) at -78 °C. The reaction mixture was left for 10 minutes and allowed to warm to room temperature before adding 2-chloro-4-(trifluoromethyl)pyrimidine (700mg,

3.85mmol). The reaction mixture was then heated to 80 °C for 1 hour and then 120 °C overnight. The reaction was then cooled to room temperature and quenched with 1 M HCI. NaHC03 (100ml_) was then added and the mixture was extracted with EtOAc (3 x 50ml_). The combined organic layers were washed with water (3 x 50ml_), brine (50ml_), dried over Na2S04 and concentrated in vacuo. The residue was purified by column chromatography using an eluent of 50% EtOAc in heptane to give ethyl 2-[4-(trifluoromethyl)pyrimidin-2-yl]acetate (788mg, 3.36mmol, 87% yield) as an orange oil.

MS Method 2: RT: 1 .49 min, m/z 235.0 [M+H] ⁺

[00454] Intermediate 38: potassium 2-[4-(trifluoromethyl)pyrimidin-2-yl]acetate

[00455] To a solution of ethyl 2-[4-(trifluoromethyl)pyrimidin-2-yl]acetate (788mg, 3.36mmol) in EtOH (3ml_) was added potassium fe/ -butoxide (566mg, 5.05mmol). The mixture was stirred at 60 °C for 4 hours. The reaction mixture was concentrated in vacuo to give a pale yellow solid which was washed with TBME and filtered to give potassium 2-[4-(trifluoromethyl)pyrimidin-2-yl]acetate (841 mg, 3.36mmol, 100% yield) as a pale yellow solid which was used in the next step without further purification.

MS Method 2: RT: 1 .09 min, m/z 206.8 [M+H] ⁺

[00456] Intermediate 39:

39a 39b

KO¾u, EtOH/H ₂ 0 Scheme 23

[00457] Intermediate 39a: potassium 2-[4-(trifluoromethyl)pyrimidin-2-yl]acetate

[00458] To a solution of 2-(trifluoromethyl)-4-pyrimidinol (4.00g, 24.38mmol) in phosphorus oxychloride (20ml_, 214.57mmol) was added a drop of Ν,Ν-dimethylformamide. The mixture was heated to 120 °C for 2 hours. The reaction mixture was then allowed to cool and concentrated in vacuo. The residue was diluted with EtOAc (100ml_) and washed with water (100ml_) and brine (100ml_). The organic layer was dried over Na2S04 and concentrated in vacuo. The residue was purified by column chromatography eluting with 50% EtOAc in heptane to give 4-chloro-2- (trifluoromethyl)pyrimidine (2.52g,13.8mmol, 56% yield) as a light brown liquid.

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 9.07 (1 H, d, J = 5.6Hz), 8.1 1 (1 H, d, J = 5.6Hz).

MS Method 3: RT: 3.61 min, m/z 182.0 [M+H] ⁺

[00459] Intermediate 39b: ethyl 2-[2-(trifluoromethyl)pyrimidin-4-yl]acetate

[00460] To a solution of sodium hydride (656mg, 16.44mmol) in DMF (2ml_) was added diethyl malonate (2.42ml_, 15.88mmol) at -78 °C. The reaction mixture was left for 10 minutes and allowed to warm to room temperature before adding 2-chloro-4-(trifluoromethyl)pyrimidine (400mg,

2.2mmol). The mixture was then heated to 80 °C for 1 hour and then 120 °C overnight. The mixture was then allowed to cool to room temperature. 1 M HCI was added to quench the reaction, then sat .aq. NaHC03 was added and the mixture was extracted with EtOAc (3 x 50ml_). The combined organic layers were washed with water (50ml_), brine (50ml_), dried over Na2S04 and concentrated in vacuo. The residue was purified by column chromatography eluting in 10% MeOH in DCM to give diethyl 2-[2-(trifluoromethyl)pyrimidin-4-yl]propanedioate (779mg, 2.54mmol, 92% yield).

MS Method 2: RT: 1 .73 min, m/z 307.0 [M+H] ⁺

[00461] Intermediate 39: potassium 2-[2-(trifluoromethyl)pyrimidin-4-yl]acetate

[00462] To a solution of diethyl 2-[2-(trifluoromethyl)pyrimidin-4-yl]propanedioate (779mg, 2.54mmol) in EtOH (3ml_) was added potassium fe/f-butoxide (428mg, 3.82mmol). The mixture was stirred at 60 °C for 4 hours. The reaction mixture was then concentrated in vacuo to give a pale yellow solid which was washed with TBME and filtered. The solid was dried in vacuo overnight to give potassium 2-[2-(trifluoromethyl)pyrimidin-4-yl]acetate (471 mg, 1 .92mmol, 75% yield) as a pale yellow solid which was used in the next step without further purification.

MS Method 2: RT: 1 .1 1 min, m/z 206.9 [M+H] ⁺

[00463] Intermediate 40

Scheme 24

[00464] Intermediate 40a: 3-(4-chlorophenyl)oxetan-3-ol

[00465] To a solution of 4-bromochlorobenzene (1 .71 g, 8.95mmol) in Et ₂ 0 (30ml_) at -78 °C, under a nitrogen atmosphere, was slowly added n-butyllithium 2.0M in heptane (4.7ml_, 9.4mmol) and the resulting clear solution was stirred at -78 °C. After 45 minutes, 3-oxetanone (630μΙ_, 9.83mmol) was added dropwise and the heterogeneous mixture was stirred overnight and allowed to warm slowly to room temperature. Water (30ml_) was then carefully added and the aqueous layer was extracted with EtOAc (2 x 30ml_). The combined organic extracts were washed with brine (30ml_), dried over Na2S04 and concentrated in vacuo. The residue was purified by flash chromatography using an eluent of 0-100% EtOAc in heptane to give 3-(4-chlorophenyl)oxetan-3-ol (1 .31 g, 7.10mmol, 79% yield) as a white waxy solid.

Ή NMR (CDC , 400MHz) δ/ppm: 7.58-7.55 (2H, m), 7.43-7.28 (2H, m), 4.93-4.86 (4H, m), 2.80 (1 H, br s).

MS Method 2: RT: 1 .13 min, m/z 207.9 [M+Na] ⁺

[00466] Intermediate 40b: ethyl 2-[4-(3-hydroxyoxetan-3-yl)phenyl]acetate

[00467] Potassium phosphate tribasic (919.8mg, 4.33mmol), 3-(4-chlorophenyl)oxetan-3-ol (200mg, 1 .08mmol), ethyl acetoacetate (0.15ml_, 1 .19mmol) and toluene (4ml_) were combined in a dry round bottomed flask under a nitrogen atmosphere. The flask was evacuated/backfilled with nitrogen then Pd(OAc)2 (12.2mg, 0.05mmol) and 'BuMePhos (33.9mg, 0.1 1 mmol) were introduced. The flask was again evacuated/backfilled with nitrogen and the mixture was stirred and heated at 90 °C overnight. The mixture was then filtered through a plug of celite and the filtrate was concentrated in vacuo. The residue was purified via column chromatography using an eluent of 0- 100% EtOAc in heptane to give ethyl 2-[4-(3-hydroxyoxetan-3-yl)phenyl]acetate (190mg, 0.80mmol, 74%) as a dark thick oil.

Ή NMR (CDCI3, 400MHz) δ/ppm: 7.60-7.56 (2H, m), 7.38-7.35 (2H, m), 4.92 (4H, s), 4.18 (2H, q, J = 7.2Hz), 3.65 (2H, s), 2.62 (1 H, br s), 1 .62 (2H, br s), 1 .28 (3H, t, J = 7.2Hz).

MS Method 2: RT: 1 .29 min, m/z 260.0 [M+Na] ⁺

[00468] Intermediate 40: 2-[4-(3-hydroxyoxetan-3-yl)phenyl]acetic acid [00469] To a solution of ethyl 2-[4-(3-hydroxyoxetan-3-yl)phenyl]acetate (190mg, 0.80mmol) in THF (3.2ml_) was added a solution of lithium hydroxide (38mg, 1 .61 mmol) in water (1 .6ml_) and the mixture was stirred at room temperature overnight. The mixture was then acidified to pH 2-3 with aqueous 1 M HCI and extracted with EtOAc (4 x 5ml_). The combined organic layers were washed with brine (10ml_), dried over Na2S04, filtered and concentrated in vacuo. The residue was purified via column chromatography using an eluent of 0-20% MeOH in DCM to afford 2-[4-(3- hydroxyoxetan-3-yl)phenyl]acetic acid (83mg, 0.40mmol, 50% yield) as a thick oil.

Ή NMR (CDC , 400MHz) δ/ppm: 7.57-7.53 (2H, m), 7.33-7.28 (2H, m), 4.88 (4H, m), 3.62 (2H, s), 2.89 (2H, br s).

MS Method 2: RT: 1 .29 min, m/z 232.0 [M+Na] ⁺

[00470] Intermediate 41

41 a 41

Scheme 25

[00471] Intermediate 41a: 2-(6-chloro-3-pyridyl)propan-2-ol

[00472] To a solution of 5-bromo-2-chloropyridine (1 .75g, 9.09mmol) in Et ₂ 0 (45ml_) at -78 °C, under a nitrogen atmosphere, was slowly added n-butyllithium 2M in heptane (4.8ml_, 9.6mmol) and the resulting orange heterogeneous mixture was stirred at -78 °C for 30 minutes. Acetone (1 ml_, 13.62mmol) was added dropwise and the resulting solution was stirred for an additional 45 minutes at -78 °C. Water (30ml_) was carefully added and the mixture was stirred at room temperature for 15 minutes. The two layers were separated and the aqueous layer extracted with EtOAc (2 x 30ml_). The combined organic layers were washed with brine (50ml_), dried over Na2S04 and concentrated in vacuo. Purification by chromatography using an eluent of 0-10% EtOAc in heptane afforded 2-(6- chloro-3-pyridyl)propan-2-ol (986mg, 5.74mmol, 63% yield) as a tan crystalline solid.

Ή NMR (CDCI3, 400MHz) δ/ppm: 8.48 (1 H, d, J = 2.4Hz), 7.80 (1 H, dd, J = 8.4Hz, 2.4Hz), 7.29 (1 H, d, J = 8.4Hz), 2.40 (1 H, br s), 1 .60 (6H, s).

MS Method 2: RT: 1 .18 min, m/z 172.6 [M+H] ⁺

[00473] Intermediate 41 : 2-(6-amino-3-pyridyl)propan-2-ol

[00474] 2-(6-Chloro-3-pyridyl)propan-2-ol (200mg, 1 .17mmol), Pd ₂ (dba) ₃ (107mg, 0.12mmol), CyJohnPhos (82mg, 0.23mmol) and dry THF (3.5ml_) were combined in a sealed tube. The tube was evacuated/backfilled with nitrogen then sealed. Lithium bis(trimethylsilyl)amide (1 .0M in toluene, 3.5ml_, 3.5mmol) was added and the mixture was heated at 90 °C overnight. After cooling to room temperature, the silylamide was deprotected by adding two drops of 1 M HCI. The mixture was filtered through a plug of celite and the solid was washed with EtOAc. The filtrate was concentrated in vacuo and the residue purified by column chromatography using an eluent of 0-20% MeOH in DCM to give 2-(6-amino-3-pyridyl)propan-2-ol (69mg, 0.45mmol, 39% yield) as a white solid.

Ή NMR (CD3OD, 400MHz) δ/ppm: 8.48 (1 H, dd, J = 2.4Hz, 0.8Hz), 7.61 (1 H, dd, J = 8.4Hz, 2.4Hz), 6.58 (1 H, dd, J = 8.8Hz, 0.8Hz), 1 .51 (6H, s) exchangeable protons not seen.

MS Method 3: RT: 0.71 min, m/z 153.1 [M+H] ⁺

[00475] Intermediate 42

Scheme 26

[00476] Intermediate 42a: 3-(4-chlorophenyl)oxetan-3-ol

[00477] To a suspension of 1 ,4-dibromobenzene (1 .19ml_, 9.28mmol) in dry Et20 (30mL) at - 78 °C, under a nitrogen atmosphere, was slowly added n-butyllithium 2.7M solution in heptane (3.6ml_, 9.72mmol) and the mixture was stirred at -78 °C for 45 minutes. 3-Oxetanone (0.65ml_, 10.14mmol) was then added and the mixture was allowed to slowly warm to room temperature and stir overnight. Water (30ml_) was slowly added and the two phases were separated. The aqueous layer was extracted with EtOAc (3 x 30ml_). The combined organic layers were washed with brine (40ml_), dried over Na2S04 and concentrated in vacuo. The residue was purified by flash chromatography using an eluent of 0-100% EtOAc in heptane to give 3-(4-bromophenyl)oxetan-3-ol (1 .23g, 5.36mmol, 58% yield) as a white solid.

Ή NMR (CDCI3, 400MHz) δ/ppm: 7.59-7.56 (2H, m), 7.53-7.50 (2H, m), 4.93-4.87 (4H, m), 2.70 (1 H, br s).

MS Method 2: RT: 1 .38 min, m/z 210.8/212.8 [M-OH] ⁺

[00478] Intermediate 42: 3-(4-chlorophenyl)oxetan-3-ol

[00479] Tris(dibenzylideneacetone)dipalladium(0) (77mg, 0.08mmol), 4,5-bis(diphenylphosphino)- 9,9-dimethylxanthene (65mg, 0.1 1 mmol), 3-(4-bromophenyl)oxetan-3-ol (319mg, 1 .39mmol), caesium carbonate (1 .36g, 4.18mmol), 1 ,4-Dioxane (7ml_) and benzophenone imine (0.28ml_, 1 .67mmol) were combined in a round bottomed flask. The flask was evacuated/backfilled with nitrogen and the mixture was stirred and heated at 100 °C overnight. The mixture was then filtered through a plug of celite and the solid washed with EtOAc (50ml_). The filtrate was concentrated in vacuo and the residue purified by flash chromatography using an eluent of 0-100% EtOAc in heptane to give 3-[4-(benzhydrylideneamino)phenyl]oxetan-3-ol) as a tan solid. This was then dissolved in MeOH (15ml_) and sodium acetate (155mg, 1 .89mmol) and hydroxylamine

hydrochloride (98mg, 1 .41 mmol) added. The mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was dissolved in a small amount of MeOH and passed through a Si-carbonate column, eluting with MeOH. The filtrate was concentrated in vacuo and the residue purified by flash chromatography using an eluent of 0-20% MeOH in DCM to give 3-(4- aminophenyl)oxetan-3-ol (123mg, 0.75mmol, 53.8% over 2 steps) as a tan solid. Ή NMR (DMSO-d6, 400MHz) δ/ppm: 7.22-7.18 (2H, m), 6.58-6.55 (2H, m), 5.96 (1 H, s), 5.02 (2H, br s), 4.68-4.61 (4H, m).

MS Method 2: RT: 0.33 min, m/z 165.8 [M+H] ⁺

[00480] Intermediate 43

43a 43

Scheme 27

[00481] Intermediate 43a: ethyl 2-(2,3-dihydro-1 ,4-benzoxazin-4-yl)acetate

[00482] A flask containing 3,4-dihydro-2H-1 ,4-benzoxazine (200mg, 1 .48mmol), ethyl bromoacetate (0.23ml_, 2.07mmol), potassium carbonate (409mg, 2.96mmol) and sodium iodide (333mg, 2.22mmol) in DMF (2ml_) was heated to 125 °C and left to stir overnight. The reaction mixture was quenched with water (50ml_) and extracted using EtOAc (3 x 50ml_). The combined organic layers were dried over Na2S04, filtered and solvent removed in vacuo to give ethyl 2-(2,3- dihydro-1 ,4-benzoxazin-4-yl)acetate (325mg,1 .47mmol, 99% yield) as a yellow oil which was used in next step without further purification.

Ή NMR (CDCb, 400MHz) δ/ppm: 6.84 - 6.79 (2H, m), 6.69-6.64 (1 H, m), 6.55-6.51 (1 H, m), 4.38-

4.28 (2H, m), 4.20 (2H, q, J = 7.1 Hz), 4.02 (2H, s), 3.53 - 3.49 (2H, m), 1 .26 (3H, t, J = 7.1 Hz). MS Method 2: RT: 1 .63 min, m/z 222.1 [M+H] ⁺

[00483] Intermediate 43: 2-(2,3-dihydro-1 ,4-benzoxazin-4-yl)acetic acid

[00484] To a flask containing ethyl 2-(2,3-dihydro-1 ,4-benzoxazin-4-yl)acetate (328mg, 1 .48mmol) in EtOH (2ml_), was added potassium fe/ -butoxide (249mg, 2.22mmol) and water (0.04ml_,

2.22mmol). The reaction mixture was heated to 60 °C and left to sir over the weekend. The reaction mixture was then quenched with 1 M NaHCO3 (50ml_) and extracted using EtOAc (50ml_). The aqueous layer was acidified to ~ pH 2 using 1 M HCI while cooling over ice. This was then extracted with EtOAc (3 x 25ml_) and the combined organic layers dried over Na2S04, filtered and solvent removed in vacou to give 2-(2,3-dihydro-1 ,4-benzoxazin-4-yl)acetic acid (260mg,1 .34mmol, 91 % yield) as a green solid which was used in the next step without further purification.

Ή NMR (CDC , 400MHz) δ/ppm: 6.87-6.82 (2H, m), 6.75-6.67 (1 H, m), 6.58-6.54 (1 H, m), 4.34-

4.29 (2H, m), 4.06 (2H, s), 3.52-3.48 (2H, m) exchangeable proton not seen.

MS Method 2: RT: 1 .27 min, m/z 193.9 [M+H] ⁺

[00485] Intermediate 44 HCI,

eOH

Scheme 28

[00486] Intermediate 44a: 2-[4-bromo-2-(hydroxymethyl)phenyl]propan-2-ol

[00487] Bromo(methyl)magnesium (4.5mL, 9.99mmol) was slowly added to a solution of 5-bromo- 3H-isobenzofuranone (850mg, 3.99mmol) in dry THF (40mL) at 0 °C, under a nitrogen atmosphere, and the mixture was stirred at room temperature overnight. The mixture was cooled to 0 °C and sat. aq. NH4CI (30ml_) was slowly added. The two layers were separated and the aqueous extracted with EtOAc (3 x 30ml_). The combined organic layers were washed with brine (50ml_), dried over Na2S04, filtered and concentrated in vacuo. The crude product was filtered through a plug of silica gel using an eluent of 50% EtOAc in heptane. The filtrate was concentrated to afford 2-[4-bromo-2- (hydroxymethyl)phenyl]propan-2-ol (918mg, 3.74mmol, 94% yield) as a light grey solid which was used in the next step without further purification.

Ή NMR (CDCI3, 400MHz) δ/ppm: 7.49 (1 H, d, J = 2.0Hz), 7.39 (1 H, dd, J = 8.4Hz, 2.0Hz), 7.18 (1 H, d, J = 8.4Hz), 4.80 (2H, d, J = 3.2Hz), 3.58 (1 H, br s), 2.99 (1 H, br s), 1 .67 (6H, s).

MS Method 2: RT: 1 .40 min, m/z 208.8/210.8 [M+H] ⁺

[00488] Intermediate 44b: 6-bromo-3,3-dimethyl-1 H-isobenzofuran

[00489] Phosphoric acid (85 wt-%, 4ml_, 68.78mmol) was added to a suspension of 2-[4-bromo-2- (hydroxymethyl)phenyl]propan-2-ol (906mg, 3.7mmol) in toluene (12ml_) and the mixture was heated at 80 °C for 3 hours. The mixture was cooled to room temperature and diluted with water. The two layers were separated and the aqueous layer neutralized with 1 M NaOH and then extracted with EtOAc (2 x 20ml_). The combined organic layers were washed with brine (20ml_), dried over Na2S04, filtered and concentrated in vacuo to give 6-bromo-3,3-dimethyl-1 /-/- isobenzofuran (588mg, 2.59mmol, 70% yield) as a brown oil.

Ή NMR (CDCI3, 400MHz) δ/ppm: 7.43-7.39 (1 H, m), 7.36-7.34 (1 H, m), 7.01 (1 H, d, J = 7.6Hz), 5.05 (2H, s), 1 .50 (6H, s).

MS Method 2: RT: 1 .83 min, m/z 226.9/228.9 [M-H] ^"

[00490] Intermediate 44: 1 ,1 -dimethyl-3H-isobenzofuran-5-amine [00491] 6-Bromo-3,3-dimethyl-1 /-/-isobenzofuran (250mg, 1 .10mmol), 4,5-bis(diphenylphosphino)- 9,9-dimethylxanthene (51 mg, 0.09mmol), tris(dibenzylideneacetone)dipalladium(0) (60mg, 0.07mmol), caesium carbonate (1 .08g, 3.3mmol), 1 ,4-dioxane (5.5ml_) and benzophenone imine (220μΙ_, 1 .31 mmol) were combined in a round bottomed flask and stirred. The flask was evacuated/backfilled with nitrogen and the mixture was heated at 100 °C overnight. The mixture was then cooled to room temperature and filtered through a plug of celite and the solid was washed with EtOAc. The filtrate was concentrated in vacuo and the residue purified by flash

chromatography using an eluent of 0-100% EtOAc in heptane to give N-(1 ,1 -dimethyl-3/-/- isobenzofuran-5-yl)-1 ,1 -diphenyl-methanimine (286mg, 0.87mmol, 79% yield) as a yellow sticky oil. This was then dissolved in MeOH (17.5ml_) and stirred at room temperature. Sodium acetate (172mg, 2.10mmol) and hydroxylamine hydrochloride (109mg, 1 .57mmol) were then added and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo and the residue dissolved in a small amount of MeOH and passed through a Si-carbonate column, eluting with MeOH. The filtrate was concentrated in vacuo and the residue purified by flash column chromatography using an eluent of 0-100% EtOAc in heptane to give 1 ,1 -dimethyl-3/-/- isobenzofuran-5-amine (120mg, 0.73mmol, 67% yield over 2 steps) as a white powder.

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 7.85 (1 H, d, J = 8.0Hz), 6.47-6.41 (1 H, m), 6.40-6.37 (1 H, m), 4.98 (2H, br s), 4.79 (2H, s), 1 .33 (6H, s).

[00492] MS Method 2: RT: 0.84 min, m/z 163.9 [M+H] ⁺

[00493] Intermediate 45

Scheme 29

[00494] Intermediate 45a: 2-(5-bromo-2-pyridyl)propan-2-ol

[00495] To a solution of methyl 5-bromopyridine-2-carboxylate (2.1 g, 9.72mmol) in dry THF (48ml_) at 0 °C, under nitrogen, was slowly added bromo(methyl)magnesium 2.7M in Εί∑0 (10.8ml_,

29.16mmol). The resulting solution was allowed to warm to room temperature and stirred overnight.

The reaction was then quenched by the dropwise addition of sat. aq. NH4CI (2ml_) then diluted with sat. aq. NaHC03 (30ml_). The aqueous layer was extracted with EtOAc (2 x 30ml_). The combined organic extracts were washed with brine (30ml_), dried over Na2S04 and concentrated in vacuo. The crude material was purified by flash column chromatography using an eluent of 0-100% EtOAc in heptane to give 2-(5-bromo-2-pyridyl)propan-2-ol (1 .43g, 6.64mmol, 68% yield) as a yellow oil.

Ή NMR (CDCI3, 400MHz) δ/ppm: 7.89 (1 H, m), 7.83 (1 H, dd, J = 8.4Hz, 2.4Hz), 7.33 (1 H, dd, J =

8.4Hz, 0.8Hz), 4.41 (1 H, br s), 1 .55 (6H, s).

MS Method 2: RT: 1 .31 min, m/z 217.8 [M+H] ⁺

[00496] Intermediate 45: 2-(5-amino-2-pyridyl)propan-2-ol [00497] In a dry round bottomed flask, under a nitrogen atmosphere, were successively introduced Pd ₂ (dba) ₃ (76mg, 0.08mmol), Xantphos (64mg, 0.1 1 mmol), CS2CO3 (1 .36g, 4.17mmol), 2-(5-bromo- 2-pyridyl)propan-2-ol (300mg, 1 .39mmol) in 1 ,4-dioxane (7mL), and benzophenone imine (0.28ml_, 1 .67mmol). The flask was evacuated/backfilled with nitrogen and the mixture was heated at 100 °C overnight. The mixture was filtered through a plug of celite and the solid washed with EtOAc. The filtrate was concentrated and the residue was purified via column chromatography using an eluent of 0-100% EtOAc in heptane to afford an orange oil (2-[5-(benzhydrylideneamino)-2-pyridyl]propan- 2-ol contaminated with benzophenone/benzophenone imine). The intermediate (400mg) was then dissolved in MeOH (25ml_). Sodium acetate (249mg, 3.03mmol) and hydroxylamine hydrochloride (158mg, 2.28mmol) were then added. The mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was dissolved in a small amount of MeOH and passed through a Si-carbonate cartridge. The product was eluted with MeOH and the filtrate was concentrated. The residue was purified via column chromatography using an eluent of 0-20% MeOH in DCM to give 2-(5-amino-2-pyridyl)propan-2-ol (120mg, 0.79mmol, 60% over 2 steps) as a light brown oil.

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 7.82 (1 H, dd, J = 2.8Hz, 0.8Hz), 7.28 (1 H, dd, J = 8.4Hz, 0.8Hz), 6.91 (1 H, dd, J = 8.4Hz, 2.8Hz), 5.15 (2H, br s), 4.93 (1 H, s), 1 .36 (6H, s).

MS Method 2: RT: 0.34 min, m/z 152.9 [M+H] ⁺

[00498] Intermediate 46

46a 46

Scheme 30

[00499] Intermediate 46a: ethyl 2-(6-fluoro-3,4-dihydro-2H-quinolin-1 -yl)acetate

[00500] A flask containing 6-fluoro-1 ,2,3,4-tetrahydroquinoline (0.19ml_, 1 .32mmol), ethyl bromoacetate (0.21 mL, 1 .85mmol), potassium carbonate (365mg, 2.65mmol) and sodium iodide (297mg, 1 .98mmol) in DMF (2ml_) was heated to 125 °C and left to stir overnight. The reaction was quenched with water (50ml_) and extracted using EtOAc (3 x 25ml_). The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo to give ethyl 2-(6-fluoro-3,4-dihydro-2H- quinolin-1 -yl)acetate (310mg,1 .30mmol, 99% yield) as an orange oil which was used in the next step without further purification.

Ή NMR (CDCI3, 400MHz) δ/ppm: 6.75-6.68 (2H, m), 6.35-6.29 (1 H, m), 4.18 (2H, q, J = 7.1 Hz),

3.97 (2H, s), 3.37 (2H, t, J = 5.7Hz), 2.77 (2H, t, J = 6.2Hz), 1 .99 (2H, p, J = 6.0Hz), 1 .25 (3H, t, J = 7.1 Hz).

MS Method 2: RT: 1 .84 min, m/z 237.9 [M+H] ⁺

[00501] Intermediate 46: 2-(6-fluoro-3,4-dihydro-2H-quinolin-1 -yl)acetic acid [00502] To a flask containing ethyl 2-(6-fluoro-3,4-dihydro-2H-quinolin-1 -yl)acetate (310mg, 1 .31 mmol) in EtOH (2ml_), was added potassium fe/ -butoxide (220mg, 1 .96mmol) and water (0.04ml_, 1 .96mmol). The reaction mixture was heated to 60 °C and left to stir over the weekend. The reaction was quenched with 1 M NaHC03 (50ml_) and extracted using EtOAc (50ml_). The aqueous layer was acidified to ~ pH 2 using 1 M HCI while cooling over ice. This was then extracted with EtOAc (3 x 25ml_). The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo to give 2-(6-fluoro-3,4-dihydro-2H-quinolin-1 -yl)acetic acid (270mg, 1 .29mmol, 99% yield) as an orange oil which was used in the next step without further purification. Ή NMR (CDCIs, 400MHz) δ/ppm: 6.81 -6.72 (2H, m), 6.42-6.36 (1 H, m), 4.00 (2H, s), 3.37 (2H, t, J = 5.7Hz), 2.81 (2H, t, J = 6.5Hz), 2.061 .99 (2H, m) exchangeable proton not seen.

MS Method 2: RT: 1 .48 min, m/z 209.9 [M+H] ⁺

[00503] Intermediate 47

47a 47

Scheme 31

[00504] Intermediate 47a: 3-chloro-5-(trifluoromethyl)pyridazine

[00505] To a solution of 5-trifluoromethyl-2/-/-pyridizan-3-one (1 .00g, 6.09mmol) in phosphorus oxychloride (5ml_, 53.64mmol) was added a drop of Ν,Ν-dimethylformamide. The mixture was heated to 120 °C for 2 hours. The reaction mixture was then allowed to cool to room temperature and concentrated in vacuo. The residue was diluted with EtOAc (100ml_) and washed with water (100ml_) and brine (100ml_). The organic layer was dried over Na2S04 and concentrated in vacuo. The residue was purified by column chromatography using an eluent of 50% EtOAc in heptane to give 3-chloro-5-(trifluoromethyl)pyridazine (0.71 g, 3.89mmol, 64% yield) as an orange liquid.

MS Method 2: 1 .27 min, m/z 182.9 [M+H] ⁺

[00506] Intermediate 47: 5-(trifluoromethyl)pyridazin-3-amine

[00507] A solution of 3-chloro-5-(trifluoromethyl)pyridazine (236mg, 1 .29mmol) and ammonium hydroxide (0.05ml_, 1 .29mmol) in THF (2ml_) was heated in a microwave reactor at 100 °C for 1 hour. Additional ammonium hydroxide (0.05ml_, 1 .29mmol) was added and the reaction mixture heated in the microwave at 100 °C for 1 hour. Additional ammonium hydroxide (0.05ml_, 1 .29mmol) was then added and the reaction mixture heated in the microwave at 100 °C for a further 8 hours. The reaction mixture was then diluted with water (50ml_) and extracted with DCM (50ml_). The organic layer was dried over Na2S04, filtered and concentrated in vacuo to give 5- (trifluoromethyl)pyridazin-3-amine (150mg, 0.92mmol, 71 % yield) as an orange powder which was used in the next step without further purification.

MS Method 2: RT: 0.79 min, m/z 163.8 [M+H] ⁺ [00508] Intermediate 48

Scheme 32

[00509] Intermediate 48: 3-amino-N-methyl-benzamide

[00510] A solution of ethyl 3-aminobenzoate (0.18ml_, 1 .21 mmol), methylamine (0.44ml_, 12.1 1 mmol) and sodium methoxide (6mg, 0.03mmol) in MeOH (2ml_) was left to stir at room temperature for 3 days. MeOH was removed in vacuo and DCM (50ml_) and water (50ml_) were added to the residue. The organic layer was separated and the aqueous extracted with DCM (3 x 20ml_) The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo to give 3-amino-N-methyl-benzamide (170mg,1 .13mmol, 93% yield) as a yellow oil which was used in the next step without further purification.

Ή NMR (CDCb, 400MHz) δ/ppm: 7.20 (1 H, t, J = 7.8Hz), 7.15 (1 H, t, J = 2.0Hz), 7.05 (1 H, ddd, J = 7.6Hz, 1 .6Hz, 1 .0Hz), 6.80 (1 H, dd, J = 8.0Hz, 2.4Hz), 6.14 (1 H, br s), 3.70 (2H, br s), 3.01 (3H, d, J = 4.9Hz).

MS Method 2: RT: 0.36 min, m/z 151 .0 [M+H] ⁺

[00511] Intermediate 49

Scheme 33

[00512] Intermediate 49a: 5-(trifluoromethyl)-1 H-pyridazin-6-one

[00513] To a solution of ethyl 3,3,3-trifluoropyruvate (2.0ml_, 15.09mmol) and acetaldehyde (0.85ml_, 15.09mmol) in DCM (25ml_) was added L-proline (677mg, 5.88mmol). The reaction mixture was stirred at room temperature for 2 hours. Water (50ml_) was then added and extracted with DCM (3 x 50ml_). The combined organic layers were washed with brine (100ml_), dried over Na2S04 and concentrated in vacuo to give ethyl 2-hydroxy-4-oxo-2-(trifluoromethyl)butanoate. This was then dissolved in EtOH (25ml_) and hydrazine hydrate (0.92ml_, 18.91 mmol) added. The mixture was stirred at reflux for 4 hours. The mixture was then cooled to room temperature and concentrated in vacuo and the resulting residue was diluted with EtOAc (100ml_) and washed with water (100ml_). The aqueous layer was extracted with EtOAc (3 x 100ml_) and the combined organic layers were washed with brine (100ml_), dried over Na2S04 and concentrated in vacuo. The residue was purified by column chromatography using an eluent of 50 % EtOAc in heptane to give 5-(trifluoromethyl)-1 /-/-pyridazin-6-one (0.76g, 4.64mmol, 37% yield) as an orange oil.

MS Method 2: RT: 0.86 min, m/z 164.7 [M+H] ⁺

[00514] Intermediate 49b: 3-chloro-4-(trifluoromethyl)pyridazine

[00515] To a solution of 5-(trifluoromethyl)-1 /-/-pyridazin-6-one (0.76g, 4.64mmol) in phosphorus oxychloride (4.33ml_, 46.44mmol) was added a drop of Ν,Ν-dimethylformamide. The mixture was heated to 120 °C for 2 hours. The reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was diluted with EtOAc (100ml_) and washed with water (100ml_) and brine (100ml_). The organic layer was dried over Na2S04 and concentrated in vacuo to give 3-chloro-4-(trifluoromethyl)pyridazine (0.51 g, 2.82mmol, 61 % yield) as a brown oil which was used in the next step without further purification.

MS Method 2: RT: 1 .29 min, m/z 182.9 [M+H] ⁺

[00516] Intermediate 49c: diethyl 2-[4-(trifluoromethyl)pyridazin-3-yl]propanedioate

[00517] Diethyl malonate (0.65ml_, 4.23mmol) was added dropwise to a suspension of sodium hydride 60% dispersion in mineral oil (226mg, 5.64mmol) in 1 ,4-dioxane (30ml_) at 0 °C under a nitrogen atmosphere. The mixture stirred at 0 °C for 30 minutes. The reaction was then allowed to warm to room temperature and 3-chloro-4-(trifluoromethyl)pyridazine (0.52g, 2.82mmol) was added portionwise. The reaction was then stirred at reflux overnight. The reaction was then allowed to cool to room temperature and concentrated in vacuo. The residue was dissolved in EtOAc (100ml_) and this was washed with sat. aq. NaHC03 (2 x 50ml_) followed by sat. aq. NhUCI (2 x 50ml_). The organic layer was dried over Na2S04, filtered and concentrated in vacuo. The crude material was purified by flash chromatography using an eluent of 50 % EtOAc in heptane to give diethyl 2-[4- (trifluoromethyl)pyridazin-3-yl]propanedioate (127mg, 0.41 mmol, 15% yield) as a yellow oil.

MS Method 2: RT: 1 .56 min, m/z 306.9 [M+H] ⁺

[00518] Intermediate 49: lithium 2-[4-(trifluoromethyl)pyridazin-3-yl]acetate

[00519] A solution of diethyl 2-[4-(trifluoromethyl)pyridazin-3-yl]propanedioate (127mg, 0.41 mmol) and lithium hydroxide (20mg, 0.83mmol) in MeOH: Water (3: 1 , 40ml_) was stirred at room temperature overnight. Further lithium hydroxide (20mg, 0.83mmol) was then added and the reaction stirred overnight. Lithium hydroxide (20mg, 0.83mmol) was again added and the reaction stirred overnight at 30 °C. Lithium hydroxide (20mg, 0.83mmol) was again added and stirred overnight at 30 °C, followed by further lithium hydroxide (20mg, 0.83mmol) and stirring overnight at 60 °C. Finally, more lithium hydroxide (20mg, 0.83mmol) was added and the reaction stirred over the weekend at 60 °C. The reaction was then allowed to cool to room temperature. MeOH was then removed in vacuo and the resulting residue was reconstituted with H2O (40ml_). The aqueous mixture was washed with Et20 (3 x 40ml_) and then the aqueous layer was concentrated in vacuo to give lithium 2-[4-(trifluoromethyl)pyridazin-3-yl]acetate (56mg, 0.26mmol, 64% yield) as an orange powder which was used in the next step without further purification.

MS Method 2: RT: 0.95 min, m/z 206.9 [M+H] ⁺

[00520] Intermediate 50

Scheme 34

[00521] Intermediate 50a: 2-(5-bromo-2-pyridyl)propan-2-ol

[00522] n-Butyl lithium (2.47M in heptane, 4ml_, 9.88mmol) was added dropwise to a suspension of 5-bromo-2-iodopyridine (2.67g, 9.41 mmol) in Et20 (45ml_) at -78 °C under a nitrogen atmosphere, and the orange solution was stirred at -78 °C for 30 minutes. Acetone (1 .05ml_, 14.3mmol) was then added dropwise and the reaction mixture was allowed to warm slowly to room temperature overnight. Water (30ml_) was then carefully added and the aqueous layer was extracted with EtOAc (2 x 30ml_). The combined organic extracts were washed with brine (30ml_), dried over Na2S04, filtered and concentrated in vacuo. The residue was purified via column chromatography using an eluent of 0-100% EtOAc in heptane to afford 2-(5-bromo-2-pyridyl)propan-2-ol (1 .41 g, 6.52mmol, 69% yield) as a light yellow oil.

Ή NMR (CDCI3, 400MHz) δ/ppm: 8.59 (1 H, dd, J = 2.0Hz, 0.8Hz), 7.84 (1 H, dd, J = 8.4Hz, 2.0Hz), 7.33 (1 H, dd, J = 8.4Hz, 0.8Hz), 4.44 (1 H, br s), 1 .55 (6H, s).

MS Method 3: RT: 3.20 min, m/z 216.0/218.0 [M+H] ⁺

[00523] Intermediate 50b: 5-bromo-2-(1 -methoxy-1 -methyl-ethyl)pyridine

[00524] To a solution of 2-(5-bromo-2-pyridyl)propan-2-ol (650mg, 3.01 mmol) in anhydrous DMF (13ml_) at 0 °C, under nitrogen, was added sodium hydride (60% dispersed in mineral oil, 241 mg, 6.03mmol) in one portion. The mixture was stirred at room temperature for 30 minutes then iodomethane (380μΙ_, 6.1 mmol) was added dropwise. After 1 hour at room temperature, water (20ml_) was carefully added followed by brine (20ml_). The aqueous solution was extracted with EtOAc (3 x 20ml_). The combined organic extracts were dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by column chromatography using an eluent of 0- 100% EtOAc in heptane to give 5-bromo-2-(1 -methoxy-1 -methyl-ethyl)pyridine (198mg, 0.86mmol, 29% yield) as a light yellow liquid.

Ή NMR (CDC , 400MHz) δ/ppm: 8.62 (1 H, dd, J = 2.4Hz, 0.8Hz), 7.82 (1 H, dd, J = 8.4Hz, 2.4Hz), 7.48 (1 H, dd, J = 8.4Hz, 0.8Hz), 3.19 (3H, s), 1 .55 (6H, s).

MS Method 3: RT: 4.14 min, m/z 230.0/232.0 [M+H] ⁺

[00525] Intermediate 50: 6-(1 -methoxy-1 -methyl-ethyl)pyridin-3-amine

[00526] In an oven-dried and nitrogen purged sealed tube were successively introduced 5-bromo- 2-(1 -methoxy-1 -methyl-ethyl)pyridine (192mg, 0.83mmol) in toluene (1 ml_), Pd2(dba)3 (38mg, 0.04mmol) and tri-te/if-butylphosphonium tetrafluoroborate (48mg, 0.17mmol) . The tube was evacuated/backfilled with nitrogen then sealed. Lithium bis(trimethylsilyl)amide (1 .0M in toluene, 1 .7ml_, 1 .7mmol) was added and the mixture was thermally heated at 50 °C overnight. After cooling to room temperature, the reaction mixture was diluted with Εί∑0 (20ml_) and the silylamide was deprotected by adding two drops of 1 M HCI. The organic layer was washed with sat. aq. NaHCC (10ml_), dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by column chromatography using an eluent of 0-100% EtOAc in heptane to afford 6-(1 -methoxy-1 -methyl- ethyl)pyridin-3-amine (47mg, 0.28mmol, 34% yield) as a brown oil that solidify upon standing.

Ή NMR (CDCI3, 400MHz) δ/ppm: 8.07 (1 H, d, J = 2.8Hz), 7.33 (1 H, d, J = 8.4Hz), 7.48 (1 H, dd, J = 8.4Hz, 2.8Hz), 3.66 (2H, br s), 3.13 (3H, s), 1 .55 (6H, s).

MS Method 2: RT: 0.45 min, m/z 167.6 [M+H] ⁺

[00527] Intermediate 51

[00528] Intermediate 51a: methyl 4-bromo-2-(bromomethyl)benzoate [00529] A mixture of methyl 4-bromo-2-methylbenzoate (2.5g, 10.91 mmol) and NBS (1 .94g, 10.91 mmol) in acetonitrile (22ml_) was degassed and AIBN (72mg, 0.44mmol) added. The mixture was stirred and heated at 80 °C overnight and then cooled to room temperature and concentrated in vacuo. The residue was purified by column chromatography using an eluent of 0-25% EtOAc in heptane to give methyl 4-bromo-2-(bromomethyl)benzoate (2.44g, 7.91 mmol, 72%) as a colourless oil that solidified upon standing.

Ή NMR (CDC , 400MHz) δ/ppm: 7.87 (1 H, d, J = 8.4Hz), 7.65 (1 H, d, J = 2.0Hz), 7.53 (1 H, dd, J =

8.4Hz, 2.0Hz), 4.92 (2H, s), 3.96 (3H, s).

MS Method 2: RT: 1 .90 min, m/z 226.8/228.8 [M-Br] ⁺

[00530] Intermediate 51 b: 5-bromo-2-methyl-isoindolin-1 -one

[00531] To a reaction tube containing methyl 4-bromo-2-(bromomethyl)benzoate (1 .2g, 3.9mmol) was added methylamine (2.0M in THF, 10ml_, 20mmol). The tube was sealed and the mixture was stirred and heated at 50 °C overnight. The mixture was then cooled to room temperature, filtered and the precipitate washed with THF. The filtrate was concentrated in vacuo and the residue was purified by column chromatography using an eluent of 0-100% EtOAc in heptane to give 5-bromo-2- methyl-isoindolin-1 -one (623mg, 2.75mmol, 71 % yield) as a white solid.

Ή NMR (CDCI3, 400MHz) δ/ppm: 7.73-7.68 (1 H, m), 7.64-7.56 (2H, m), 4.36 (2H, s), 3.19 (3H, s). MS Method 3: RT: 3.18 min, m/z 226.0/228.0 [M+H] ⁺

[00532] Intermediate 51 c: 2-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)isoindolin- 1 -one

[00533] A round bottomed flask containing bis(pinacolato)diboron (354mg, 1 .39mmol) and KOAc (326mg, 3.32mmol) in 1 ,4-dioxane (6.5ml_) was evacuated/backfilled with nitrogen.

Pd(dppf)Cl2.CH2Cl2 (54mg, 0.07mmol) was added and the flask was evacuated/backfilled with nitrogen again. The reaction mixture was then stirred and heated at 85 °C overnight. After this time the mixture was cooled to room temperature, filtered through a plug of celite and the solid was washed with EtOAc. The filtrate was concentrated and the residue purified by column

chromatography using an eluent of 0-100% EtOAc in heptane to give 2-methyl-5-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)isoindolin-1 -one (324mg,1 .19mmol, 89% yield) as a brown solid.

Ή NMR (CDCI3, 400MHz) δ/ppm: 7.92 (1 H, dd, J = 7.6Hz, 0.4Hz), 7.90-7.89 (1 H, m), 7.85 (1 H, dd, J = 7.6Hz, 0.4Hz), 4.39 (2H, s), 3.23 (3H, s), 1 .38 (12H, s).

MS Method 3: RT: 3.61 min, m/z 274.1 [M+H] ⁺

[00534] Intermediate 51 : 2-(2-methyl-1 -oxo-isoindolin-5-yl)acetic acid

[00535] A round bottomed flask was charged with Pd2(dba)3 (27mg, 0.03mmol), tri-1 - naphthylphosphine (36mg, 0.09mmol), ethyl bromoacetate (109μΙ_, 0.98mmol) and K3PO4 (1 .04g, 4.91 mmol). The flask was evacuated/backfilled with nitrogen then 2-methyl-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)isoindolin-1 -one (322mg, 1 .18mmol) in THF (4ml_) was added and the reaction mixture was stirred at room temperature overnight. The mixture was filtered through a plug of celite and the solid was washed with EtOAc. The filtrate was concentrated and the residue was purified by column chromatography using an eluent of 0-100% EtOAc in heptane to afford a brown oil (70mg) which was dissolved in THF (1 .2ml_). A solution of lithium hydroxide (14mg, 0.60mmol) in water (0.6ml_) was added and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (5 ml_) and the pH of the solution was adjusted to pH 2-3 with 1 M HCI. The mixture was extracted with EtOAc (5 x 5ml_). The combined organic layers were washed with brine (5ml_), dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by column chromatography using an eluent of 0-20% MeOH in DCM to afford 2-(2-methyl-1 -oxo-isoindolin-5- yl)acetic acid (34mg) as a light brown oil.

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 12.46 (1 H, br s), 7.62-7.57 (1 H, m), 7.48-7.45 (1 H, m), 7.39- 7.34 (1 H, m), 4.44 (2H, s), 3.70 (2H, s), 3.07 (3H, s).

MS Method 2: RT: 0.95 min, m/z 206.1 [M+H] ⁺

[00536] Intermediate 52

Scheme 36

[00537] Intermediate 52a: ethyl 2-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]acetate

[00538] Diisopropylamine (1 .4ml_, 9.99mmol) was slowly added to a solution of n-butyllithium (2.47M in heptane, 4ml_, 9.88mmol) in THF (8.3ml_) at 0 °C and the mixture was stirred at this temperature for 30 minutes, followed by the dropwise addition of ethyl acetoacetate (420μΙ_, 3.32mmol) and subsequent stirring at 0 °C for an additional 60 minutes. The mixture was then cooled to -78 °C, and ethyl trifluoroacetate (435μΙ_, 3.66mmol) was slowly added. The reaction mixture was allowed to warm to room temperature overnight. The mixture was cooled to 0 °C and 1 M HCI (30ml_) was added. The aqueous layer was extracted with DCM (3 x 20ml_). The combined organic extracts were washed with brine (25ml_), dried over Na2S04, filtered and concentrated in vacuo. The resulting red oil was dissolved in acetic acid (8.3ml_) and the solution was cooled to 0 °C. Methylhydrazine (210μΙ_, 3.99mmol) was slowly added. The cooling bath was then removed and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo and the residue purified by column chromatography using an eluent of 0-100% EtOAc in heptane to afford ethyl 2-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]acetate as a yellow oil (314mg, 1 .33mmol, 40% yield).

Ή NMR (CDC , 400MHz) δ/ppm: 6.48 (1 H, s), 4.22 (2H, q, J = 7.2Hz), 3.91 (3H, s), 3.72 (2H, s), 1 .30 (3H, t, J = 7.2Hz). ⁹ F NMR (CDCb, 400MHz) δ/ppm: -62.1 .

MS Method 2: RT: 1 .34 min, m/z 237.1 [M+H] ⁺

[00539] Intermediate 52: 2-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]acetic acid

[00540] To a solution of ethyl 2-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]acetate (296mg, 1 .25mmol) in THF (5ml_) was added lithium hydroxide (60mg, 2.51 mmol) in H2O (2.5ml_) and the mixture was stirred at room temperature for 2 hours. The mixture was acidified to pH 1 -2 with 1 M HCI and extracted with EtOAc (4 x 5ml_). The combined organic layers were washed with brine

(10ml_), dried over Na2S04, filtered and concentrated in vacuo to afford 2-[2-methyl-5-

(trifluoromethyl)pyrazol-3-yl]acetic acid as an orange oil (232mg, 1 .1 1 mmol, 89% yield).

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 12.77 (1 H, br s), 6.61 (1 H, s), 3.86 (2H, s), 3.82 (3H, s).

NMR (DMSO-d6, 400MHz) δ/ppm: -60.4.

MS Method 2: RT: 1 .23 min, m/z 209.0 [M+H] ⁺

[00541] Intermediate 53

53a 53b 53 Scheme 37

[00542] Intermediate 53a: [4-(methylcarbamoyl)phenyl]boronic acid

[00543] A flask containing 4-(methoxycarbonyl)benzeneboronic acid (250mg, 1 .39mmol), methylamine (0.5ml_, 13.89mmol) and sodium methoxide (0.64ml_, 2.78mmol) in MeOH (2mL) was left to stir at room temperature for 3 days. MeOH was removed in vacuo followed by the addition of water (30ml_). This was extracted with EtOAc (3 x 50ml_). The aqueous layer was reduced in vacuo and the salt obtained was dissolved in a minimum amount of MeOH and filtered to remove inorganic salts. The filtrate was collected and reduced in vacuo to give [4- (methylcarbamoyl)phenyl]boronic acid (250mg, 1 .39mmol, 100% yield) as a white solid which was used in the next step without further purification.

Ή NMR (CD3OD, 400MHz) δ/ppm: 7.80 (2H, d, J = 8.2Hz), 7.54 (2H, d, J = 8.2Hz), 2.92 (3H, s) exchangeable protons not seen.

MS Method 2: RT: 0.73 min, m/z 179.9 [M+H] ⁺

[00544] Intermediate 53b: ethyl 2-[4-(methylcarbamoyl)phenyl]acetate

[00545] A flask containing [4-(methylcarbamoyl)phenyl]boronic acid (250mg, 1 .4mmol) and potassium carbonate (386mg, 2.79mmol) in water (0.25ml_) and THF (2ml_) was degassed for 15 minutes before the addition of tris(dibenzylideneacetone)dipalladium (0) (25mg, 0.03mmol) and tri- o-tolylphosphine (21 mg, 0.07mmol) followed by ethyl bromoacetate (0.15ml_, 1 .4mmol). The reaction mixture was heated to 65 °C and left to stir at this temperature overnight. The reaction was then cooled to room temperature, filtered through celite and the filter cake washed with EtOAc. Water (50ml_) was then added to the mixture and material extracted using EtOAc (3 x 50ml_). The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by flash column chromatography using an eluent of 0-100% EtOAc in heptane to give ethyl 2-[4-(methylcarbamoyl)phenyl]acetate (1 10mg, 0.50mmol, 35% yield) as a bright yellow solid. Ή NMR (CDCb, 400MHz) δ/ppm: 7.74 (2H, d, J = 8.3Hz), 7.37 (2H, d, J = 8.4Hz), 4.18 (2H, q, J = 7.1 Hz), 3.68 (2H, s), 3.04 (3H, d, J = 4.9Hz), 1 .27 (3H, t, J = 7.1 Hz) exchangeable proton not seen. MS Method 2: RT: 1 .22 min, m/z 222.1 [M+H] ⁺

[00546] Intermediate 53: 2-[4-(methylcarbamoyl)phenyl]acetic acid

[00547] A flask containing ethyl 2-[4-(methylcarbamoyl)phenyl]acetate (1 10mg, 0.50mmol) , potassium fe/ -butoxide (84mg, 0.75mmol) and water (0.01 mL, 0.75mmol) in ethanol (2ml_) was heated to 60 °C and left to stir overnight. The reaction was quenched with 1 M NaHCC (20ml_) and extracted with EtOAc (20ml_). The aqueous layer was acidified with cone. HCI to pH 2 and then extracted with EtOAc (3 x 20ml_). The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo to give 2-[4-(methylcarbamoyl)phenyl]acetic acid (55mg, 0.19mmol, 40% yield) as an orange solid which was used in the next step without further purification.

MS Method 2: RT: 0.88 min, m/z 194.0 [M+H] ⁺

[00548] Intermediate 54

54

Scheme 38

[00549] Intermediate 54a: ethyl 2-[4-(dimethylcarbamoyl)phenyl]acetate

[00550] A flask containing 4-(dimethylcarbamoyl)-phenylboronic acid (200mg, 1 .04mmol) and potassium carbonate (286mg, 2.07mmol) in water (0.25ml_) and THF (2ml_) was degassed for 15 minutes before the addition of tris(dibenzylideneacetone)dipalladium (0) (19mg, 0.02mmol) and tri- o-tolylphosphine (16mg, 0.05mmol) followed by ethyl bromoacetate (0.1 1 ml_,

1 .04mmol). The reaction mixture was then heated to 65 °C and left to stir at this temperature over the weekend. The reaction was then quenched by the addition of water (20ml_) and extracted with EtOAc (3 x 20ml_). The combined organic extracts were dried over Na2S04, filtered and

concentrated in vacuo. The residue was purified by flash column chromatography using an eluent of 0-75% EtOAc in heptane to give ethyl 2-[4-(dimethylcarbamoyl)phenyl]acetate (142mg, 0.60mmol, 58% yield) as a pale yellow oil.

Ή NMR (CDCI ₃ , 400MHz) δ/ppm: 7.40 (2H, d, J = 8.3Hz), 7.34 (2H, d, J = 8.3Hz), 4.17 (2H, q, J = 7.1 Hz), 3.65 (2H, s), 3.1 1 (3H, s), 3.02 (3H, s), 1 .28 (3H, t, J = 7.1 Hz).

MS Method 2: RT: 1 .32 min, m/z 236.1 [M+H] ⁺

[00551] Intermediate 54: 2-[4-(dimethylcarbamoyl)phenyl]acetic acid [00552] A flask containing ethyl 2-[4-(dimethylcarbamoyl)phenyl]acetate (145mg, 0.62mmol), potassium fe/ -butoxide (104mg, 0.92mmol) and water (0.02mL, 0.92mmol) in EtOH (2ml_) was heated to 60 °C and left to stir overnight. The reaction was quenched by the addition of

water (20ml_) and extracted with EtOAc (20ml_). The aqueous layer was acidified to pH 2 with cone. HCI and extracted with EtOAC (3 x 20ml_). These organic extracts were combined and dried over Na2S04, filtered and concentrated in vacuo to give 2-[4-(dimethylcarbamoyl)phenyl]acetic acid (95mg, 0.46mmol, 74% yield) as an orange solid which was used in the next step without further purification.

Ή NMR (CDCIs, 400MHz) δ/ppm: 7.39 (2H, d, J = 8.2Hz), 7.31 (2H, d, J = 8.1 Hz), 3.64 (2H, s), 3.14 (3H, s), 3.01 (3H, s) exchangeable proton not seen.

MS Method 2: RT: 1 .01 min, m/z 208.1 [M+H] ⁺

[00553] Intermediate 55

55a 55

Scheme 39

[00554] Intermediate 55a: ethyl 2-[3-(trifluoromethyl)pyrazol-1 -yl]acetate

[00555] A solution of 3-(trifluoromethyl)-1 /-/-pyrazole (75mg, 0.55mmol) and potassium carbonate (228mg, 1 .65mmol) were left to stir in MeCN (2ml_) for 30 minutes before the addition of ethyl bromoacetate (0.09ml_, 0.83mmol). The reaction mixture was then heated to 60 °C and left to stir for 2 hours. The reaction mixture was quenched by the addition of water (20ml_) and extracted using EtOAc (3 x 20ml_). The organic layers were combined, dried over Na2S04, filtered and concentrated in vacuo to give ethyl 2-[3-(trifluoromethyl)pyrazol-1 -yl]acetate (120mg, 0.55mmol, 100% yield) as a yellow oil which was used in the next step without further purification.

Ή NMR (CDCb, 400MHz) δ/ppm: 7.55 (1 H, dd, J = 2.3Hz, 0.9Hz), 6.59 (1 H, d, J = 2.2Hz), 4.96 (2H, s), 4.25 (2H, q, J = 7.1 Hz), 1 .29 (3H, t, J = 7.1 Hz).

MS Method 2: RT: 1 .58 min, m/z 223.1 [M+H] ⁺

[00556] Intermediate 55: 2-[3-(trifluoromethyl)pyrazol-1 -yl]acetic acid

[00557] A solution of ethyl 2-[3-(trifluoromethyl)pyrazol-1 -yl]acetate (120mg, 0.54mmol) and potassium fe/ -butoxide (91 mg, 0.81 mmol) in EtOH (2ml_) and water (0.01 ml_, 0.81 mmol) was heated to 60 °C and left to stir overnight. The reaction mixture was quenched by the addition of water (20ml_) and extracted once with EtOAc (20ml_). The aqueous layer was acidified to pH 2 with cone. HCI and extracted with EtOAc (3 x 20ml_) These combined organic layers were dried over Na2S04, filtered and concentrated in vacuo to give 2-[3-(trifluoromethyl)pyrazol-1 -yl]acetic acid (90mg, 0.46mmol, 86% yield) as an orange solid.

Ή NMR (CDC , 400MHz) δ/ppm: 7.54 (1 H, dd, J = 2.3Hz, 0.9Hz), 6.61 (1 H, d, J = 2.2Hz), 5.04 (2H, s) exchangeable proton not seen.

MS Method 2: RT: 1 .18 min, m/z 195.0 [M+H] ⁺ [00558] Intermediate 56

56a 56

Scheme 40

[00559] Intermediate 56a: 1 -(diluoromethyl)-4-nitro-pyrazole

[00560] Sodium chlorodifluoroacetate (2.7g, 17.69mmol) was added to a solution of 4- nitropyrazole (1 .00g, 8.84mmol) and NaHCOs (1 .49g, 17.69mmol) in DMF (8ml_) and the solution heated to 100 °C overnight. More NaHCOs (1 .49g, 17.69mmol) and 4-nitropyrazole (1 .00g, 8.84mmol) were added and stirring was continued overnight. More NaHC03 (1 .49g, 17.69mmol) and 4-nitropyrazole (1 .0g, 8.84mmol) were added and stirring was continued overnight. The solution was then cooled to room temperature and the mixture was diluted with water (50ml_) and EtOAc

(50ml_). The insoluble precipitate was filtered off and the organic layer separated. The aqueous was extracted with EtOAc (3 x 50ml_) and the combined organic layers were washed with brine (50ml_), dried over Na2S04 and concentrated in vacuo. The residue was purified by column chromatography using an eluent of 50% EtOAc in heptane to give 1 -(difluoromethyl)-4-nitro-pyrazole (0.58g, 3.59mmol, 41 % yield) as a pale yellow oil.

Ή NMR (CDC , 400MHz) δ/ppm: 8.59 (1 H, s), 8.24 (1 H, s), 7.23 (1 H, t, J = 60.0Hz).

MS Method 2: RT: 1 .16 min, m/z 164.0 [M+H] ⁺

[00561] Intermediate 56 1 -(difluoromethyl)pyrazol-4-amine

[00562] 1 -(difluoromethyl)-4-nitro-pyrazole (0.59g, 3.59mmol) in EtOAc (72 mL) was hydrogenated by circulating through an H-Cube reactor using a 10% Pd/C CatCart overnight. The reaction mixture was then concentrated in vacuo to give 1 -(difluoromethyl)pyrazol-4-amine (455mg, 3.42mmol, 95% yield) as a pale yellow oil.

Ή NMR (CDCI3, 400MHz) δ: 7.35 (2H, s), 7.08 (1 H, t, J = 60.8Hz).

[00563] Intermediate 57

Scheme 41

[00564] Intermediate 57a: ethyl 2-[4-(trifluoromethyl)pyrazol-1 -yl]acetate [00565] 4-(Trifluoromethyl)-1 /-/-pyrazole (100mg, 0.73mmol) and potassium carbonate (305mg, 2.20mmol) were left to stir in MeCN (2ml_) for 30 minutes at room temperature before the addition of ethyl bromoacetate (0.12ml_, 1 .10mmol). The reaction mixture was then heated to 60 °C and left to stir at this temperature for 2 hours. The reaction was allowed to cool to room temperature and quenched by the addition of water (20ml_) and this solution was extracted with EtOAc (3 x 20ml_). The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo to give ethyl 2-[4-(trifluoromethyl)pyrazol-1 -yl]acetate (160mg, 0.72mmol, 100% yield) as a yellow oil. Ή NMR (CDCIs, 400MHz) δ/ppm: 7.82 (1 H, s), 7.77 (1 H, s), 4.95 (2H, s), 4.29 (2H, q, J = 7.1 Hz), 1 .32 (3H, t, J = 7.1 Hz).

MS Method 2: RT: 1 .54 min, m/z 222.9 [M+H] ⁺

[00566] Intermediate 57: 2-[4-(trifluoromethyl)pyrazol-1 -yl]acetic acid

[00567] Potassium fe/ -butoxide (121 mg, 1 .08mmol) was added to a flask containing ethyl 2-[4- (trifluoromethyl)pyrazol-1 -yl]acetate (160mg, 0.72mmol) in EtOH (2ml_) and water (0.02ml_, 1 .08mmol). The reaction mixture was heated to 60 °C and left to stir for 2 hours. The reaction was quenched by the addition of water (20ml_) and extracted with EtOAc (3 x 20ml_). The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo to give 2-[4- (trifluoromethyl)pyrazol-1 -yl]acetic acid (140mg, 0.72mmol, 100% yield) as a yellow oil which was used in the next step without further purification.

Ή NMR (CDCI3, 400MHz) δ/ppm: 8.38 (1 H, br s), 7.91 (1 H, br s), 5.05 (2H, s) exhangable proton not seen.

MS Method 2: RT: 1 .18 min, m/z 195.0 [M+H] ⁺

[00568] Intermediate 58

58a 58

Scheme 42

[00569] Intermediate 58a: ethyl 2-[3-methyl-5-(trifluoromethyl)pyrazol-1 -yl]acetate

[00570] 5-methyl-3-(trifluoromethyl)pyrazole (100mg, 0.67mmol) and potassium carbonate (276mg, 2.00mmol) were left to stir in MeCN (2ml_) for 30 minutes before the addition of ethyl bromoacetate (0.1 1 ml_, 1 .OOmmol). The reaction mixture was then heated to 60 °C and left to stir for 2 hours. The reaction was then quenched by the addition of water (20ml_) and extracted with

EtOAc (3 x 20ml_). The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo to give ethyl 2-[3-methyl-5-(trifluoromethyl)pyrazol-1 -yl]acetate (160mg, 0.67mmol, 100% yield) as a colourless oil which was used in the next step without further purification.

Ή NMR (CDCI3, 400MHz) δ/ppm: 6.36 (1 H, s), 4.91 (2H, s), 4.27 (2H, q, J = 7.1 Hz), 2.31 (3H, d, J = 0.7Hz), 1 .31 (3H, t, J = 7.2Hz). [00571] Intermediate 58: 2-[3-methyl-5-(trifluoromethyl)pyrazol-1 -yl]acetic acid

[00572] Potassium fe/ -butoxide (1 14mg, 1 .02mmol) was added to a flask containing ethyl 2-[3- methyl-5-(trifluoromethyl)pyrazol-1 -yl]acetate (160mg, 0.67mmol) in EtOH (2mL) and water (0.02ml_, 1 .02mmol). The reaction mixture was then heated to 60 °C and left to stir overnight. The reaction was then quenched by the addition of water (20ml_) and this was extracted with EtOAc (3 x 20ml_). The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo to give 2-[3-methyl-5-(trifluoromethyl)pyrazol-1 -yl]acetic acid (120mg, 0.57mmol, 85% yield) as a white solid which was used in the next step without further purification.

Ή NMR (CDCIs, 400MHz) δ/ppm: 6.43 (1 H, s), 5.00 (2H, s), 2.33 (3H, s) exhangable proton not seen.

MS Method 2: RT: 1 .37 min, m/z 209.1 [M+H] ⁺

[00573] Intermediate 59

Scheme 43

[00574] Intermediate 59a: benzyl 2-(3,5-dimethylpyrazol-1 -yl)acetate

[00575] Benzyl bromoacetate (0.2ml_, 1 .25mmol) was added to a flask containing 3,5- dimethylpyrazole (100mg, 1 .04mmol) and potassium carbonate (431 mg, 3.12mmol) in MeCN (3ml_). The reaction mixture was heated to 60 °C and left to stir overnight. The reaction was then quenched by the addition of water (20ml_) and extracted with EtOAc (3 x 20ml_). The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by column chromatography using an eluent of 0-25% EtOAc in heptane to give benzyl 2-(3,5- dimethylpyrazol-1 -yl)acetate (228mg, 0.93mmol, 90% yield) as a yellow oil.

Ή NMR (CDCb, 400MHz) δ/ppm: 7.39-7.31 (5H, m), 5.86 (1 H, s), 5.19 (2H, s), 4.80 (2H, s), 2.22 (3H, s), 2.17 (3H, s).

MS Method 2: RT: 1 .59 min, m/z 245.3 [M+H] ⁺

[00576] Intermediate 59: 2-(3,5-dimethylpyrazol-1 -yl)acetic acid

[00577] Benzyl 2-(3,5-dimethylpyrazol-1 -yl)acetate (228mg, 0.93mmol) was diluted in EtOAc (18ml_) and hydrogenated by circulating through an H-cube reactor using a 10% Pd/C CatCart for 1 hour. The reaction mixture was then reduced in vacuo to give 2-(3,5-dimethylpyrazol-1 -yl)acetic acid (120mg, 0.78mmol, 83% yield) as a pale yellow solid which was used in the next step without further purification.

MS Method 2: RT: 0.79 min, m/z 155.0 [M+H] ⁺

[00578] Intermediate 60

60 60e 60d

Scheme 44

[00579] Intermediate 60a: ethyl 1 -(difluoromethyl)pyrazole-4-carboxylate

[00580] Ethyl 1 /-/-pyrazole-4-carboxylate (3.00g, 21 .41 mmol) was added to a solution of sodium chlorodifluoroacetate (6.53g, 42.81 mmol) and NaHCOs (3.60g, 42.81 mmol) in DMF (12ml_) and the solution heated to 100 °C overnight. Sodium chlorodifluoroacetate (6.53g, 42.81 mmol) and ethyl 1 H-pyrazole-4-carboxylate (3.00g, 21 .41 mmol) was added and the reaction was left to stir overnight. Sodium chlorodifluoroacetate (6.53g, 42.81 mmol) and ethyl 1 H-pyrazole-4-carboxylate (3g, 21 .41 mmol) was added and the reaction was left to stir overnight. The solution was then cooled to room temperature and diluted with water (200ml_) and EtOAc (200ml_). The insoluble precipitate was filtered. The organic layer was separated and the aqueous was extracted with EtOAc (3 x 100ml_). The combined organic layers were washed with brine (200ml_), dried over Na2S04 and concentrated in vacuo to give ethyl 1 -(difluoromethyl)pyrazole-4-carboxylate (4.17g, 21 .41 mmol, 100% yield) as a brown oil which was used in the next step without further purification.

Ή NMR (CDC , 400MHz) δ/ppm: 8.34 (1 H, s), 8.09-8.04 (1 H, m), 7.22 (1 H, t, J = 60.4Hz), 4.35 (2H, q, J = 7.2Hz), 1 .39 (3H, t, J = 7.2Hz).

MS Method 2: RT: 1 .37 min, m/z 191 .1 [M+H] ⁺

[00581] Intermediate 60b: 1 -(difluoromethyl)pyrazole-4-carboxylic acid

[00582] Lithium hydroxide (1 .05g, 43.86mmol) was added to a solution of ethyl 1 - (difluoromethyl)pyrazole-4-carboxylate (4.17g, 21 .93mmol) in THF (10ml_) and stirred for 2 hours. The solution was diluted with water (1 OOmL) and acidified with 1 M HCI. This was extracted with EtOAc (3 x 100ml_). The combined organic layers were washed with brine, dried over Na2S04 and concentrated in vacuo to give 1 -(difluoromethyl)pyrazole-4-carboxylic acid (2.93g, 18.05mmol, 82% yield) as a colourless oil which was used in the next step without further purification.

MS Method 2: RT: 0.90 min, m/z 161 .0 [M-H] ^"

[00583] Intermediate 60c: 2-(benzotriazol-1 -yl)-1 -[1 -(difluoromethyl)pyrazol-4-yl]ethanone [00584] To a solution of 1 -(difluoromethyl)pyrazole-4-carboxylic acid (1 .00g, 6.17mmol) in toluene (50ml_) was added thionyl chloride (1 .34ml_, 18.47mmol) dropwise at room temperature. The mixture was heated to reflux for 2 hours, cooled to room temperature, and concentrated in vacuo. The solid was taken up in THF (12.8ml_) and 1 -[(trimethylsilyl)methyl]-1 /-/-benzotriazole (1 .27g, 6.17mmol) was added and heated to reflux and left overnight. The mixture was concentrated and recrystallised from EtOAc/heptane. The crystals were filtered and dried under vacuum overnight to give 2-(benzotriazol-1 -yl)-1 -[1 -(difluoromethyl)pyrazol-4-yl]ethanone (336mg, 1 .20mmol, 19% yield). The mother liquor was concentrated and the residue was purified by column chromatography eluting with 50% EtOAc in heptane to give 2-(benzotriazol-1 -yl)-1 -[1 -(difluoromethyl)pyrazol-4- yl]ethanone (617mg, 2.22mmol, 36% yield) as an orange solid.

MS Method 2: RT: 1 .44 min, m/z 278.1 [M+H] ⁺

[00585] Intermediate 60d: [(Z)-2-(benzotriazol-1 -yl)-1 -[1 -(difluoromethyl)pyrazol-4-yl]vinyl] trifluoromethanesulfonate

[00586] To a solution of 2-(benzotriazol-1 -yl)-1 -[1 -(difluoromethyl)pyrazol-4-yl]ethanone (336mg, 1 .21 mmol) and 2,6-lutidine (282μΙ_, 2.42mmol) in dry DCM (2.4ml_) at 0 °C was added

trifluoromethanesulfonic anhydride (268μΙ_, 1 .60mmol) dropwise. After 10 minutes, the ice bath was removed and the reaction mixture was stirred at room temperature overnight. The mixture was then washed with water (10ml_) and partitioned using a phase separator. The organics were

concentrated in vacuo to give [(Z)-2-(benzotriazol-1 -yl)-1 -[1 -(difluoromethyl)pyrazol-4-yl]vinyl] trifluoromethanesulfonate (290mg, 0.71 mmol, 58% yield) as a brown oil which was used in the next step without further purification.

MS Method 2: RT: 1 .81 min, m/z 410.0 [M+H] ⁺

[00587] Intermediate 60e: methyl 2-[1 -(difluoromethyl)pyrazol-4-yl]acetate

[00588] To a solution of [(Z)-2-(benzotriazol-1 -yl)-1 -[1 -(difluoromethyl)pyrazol-4-yl]vinyl] trifluoromethanesulfonate (290mg, 0.71 mmol) in dry MeCN (10ml_) at 0 °C was added sodium methoxide (188mg, 1 .42mmol). After 10 minutes, the ice bath was removed and the reaction mixture was stirred at room temperature for 2 hours before heating at reflux for a further 2 hours. The reaction was cooled to room temperature and concentrated in vacuo and the mixture was diluted with MeOH (5ml_) and HCI (0.1 mL, 0.71 mmol) was added. The mixture was heated at reflux overnight. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was taken up in EtOAc (100ml_) and washed with water (100ml_) and brine (100ml_). The organic layer was dried over Na2S04 and concentrated in vacuo to give an orange oil. The residue was taken up in MeOH and passed through an SCX cartridge washing with MeOH. The MeOH washings were concentrated in vacuo to give methyl 2-[1 -(difluoromethyl)pyrazol-4-yl]acetate (135mg, 0.71 mmol, 100% yield) as an orange oil which was used in the next step without further purification.

MS Method 2: RT: 1 .20 min, m/z 191 .1 [M+H] ⁺

[00589] Intermediate 60: 2-[1 -(difluoromethyl)pyrazol-4-yl]acetic acid [00590] Methyl 2-[1 -(difluoromethyl)pyrazol-4-yl]acetate (191 mg, 1 .OOmmol) was added to a solution of lithium hydroxide (33mg, 1 .38mmol) in THF (3ml_) and the solution heated to 70 °C over the weekend. The solution was cooled to room temperature and diluted with water (50ml_) and EtOAc (50ml_). The organic layer was separated and the aqueous was extracted with EtOAc (3 x 50ml_). The combined organic layers were washed with brine, dried over Na2S04 and concentrated in vacuo. The residue was purified by column chromatography using an eluent of 0-100% acetone in heptane to give 2-[1 -(difluoromethyl)pyrazol-4-yl]acetic acid (18mg, O.I Ommol, 15% yield) as a yellow oil.

MS Method 2: RT: 0.90 min, m/z 177.0 [M+H] ⁺

[00591] Intermediate 61

61 61 b

Scheme 45

[00592] Intermediate 61a: ethyl 2-[5-hydroxy-5-(trifluoromethyl)-4H-isoxazol-3-yl]acetate

[00593] Diisopropylamine (1 .4ml_, 9.99mmol) was slowly added to a solution of n-butyllithium (2.47M in heptane, 4ml_, 9.88mmol) in THF (8.3ml_) at 0 °C and the mixture was stirred at this temperature for 30 minutes, followed by the dropwise addition of ethyl acetoacetate (420μΙ_, 3.44mmol) and subsequent stirring at 0 °C for an additional 60 minutes. The mixture was then cooled to -78 °C, and ethyl trifluoroacetate (435μΙ_, 3.66mmol) was slowly added. The reaction mixture was allowed to warm to room temperature overnight. The mixture was cooled to 0 °C and 1 M HCI (30ml_) was added. The aqueous layer was extracted with DCM (3 x 20ml_). The combined organic extracts were washed with brine (25ml_), dried over Na2S04, filtered and concentrated in vacuo. The resulting red oil was dissolved in acetic acid (8.3ml_) and the solution was stirred and cooled to 0 °C. Hydroxylamine solution (50 wt% in H2O, 250μΙ_, 4.08mmol) was added. The cooling bath was removed and the solution was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was purified via column chromatography using an eluent of 0- 100% EtOAc in heptane to give ethyl 2-[5-hydroxy-5-(trifluoromethyl)-4H-isoxazol-3-yl]acetate (830mg, 3.44mmol, 100% yield) as a yellow oil.

Ή NMR (CDCI3, 400MHz) δ/ppm: 4.23 (2H, q, J = 7.2Hz), 3.53 (1 H, d, J = 18.8Hz), 3.52 (2H, s), 3.25 (1 H, d, J = 18.8Hz), 1 .31 (3H, t, J = 7.2Hz) exchangeable proton not seen. ⁹ F NMR (CDCI3, 400MHz) δ/ppm: -83.0. MS Method 2: RT: 1 .36 min, m/z 240.0 [M-H] ^"

[00594] Intermediate 61 b: ethyl 2-[5-(trifluoromethyl)isoxazol-3-yl]acetate

[00595] To a stirred solution of ethyl 2-[5-hydroxy-5-(trifluoromethyl)-4H-isoxazol-3-yl]acetate (830mg, 3.44mmol) and Et ₃ N (1 .45ml_, 10.4mmol) in DCM (34ml_) at 0 °C was slowly added methanesulfonyl chloride (320μΙ_, 4.13mmol) and the mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified via column chromatography using an eluent of 0-100% acetone in heptane to give ethyl 2-[5-(trifluoromethyl)isoxazol-3- yl]acetate (616mg, 2.76mmol, 80%, yield) as a yellow oil.

Ή NMR (CDC , 400MHz) δ/ppm: 6.85 (1 H, s), 4.25 (2H, q, J = 7.2Hz), 3.83 (2H, s), 1 .32 (3H, t, J = 7.2Hz). ⁹ F NMR (CDCb, 400MHz) δ/ppm: -64.2.

MS Method 2: RT: 1 .68 min, m/z 445.0 [2M+H] ⁺

[00596] Intermediate 61 : 2-[5-(trifluoromethyl)isoxazol-3-yl]acetic acid

[00597] To a solution of ethyl 2-[5-(trifluoromethyl)isoxazol-3-yl]acetate (592mg, 2.65mmol) in THF (10.6ml_) was added lithium hydroxide (127mg, 5.31 mmol) in H2O (5.3ml_) and the mixture was stirred at room temperature for 2 hours. The mixture was acidified to pH 1 -2 with 1 M HCI and extracted with EtOAc (3 x 10ml_). The combined organic layers were washed with brine (10ml_), dried over Na2S04, filtered and concentrated in vacuo to afford 2-[5-(trifluoromethyl)isoxazol-3- yl]acetic acid (489mg, 2.51 mmol, 94% yield) as a white solid.

Ή NMR (CDCI3, 400MHz) δ/ppm: 6.85 (1 H, s), 3.92 (2H, s) exchangeable proton not seen. ⁹ F NMR (CDCI3, 400MHz) δ/ppm: -64.2.

MS Method 2: RT: 1 .36 min, m/z 194.1 [M-H] ^"

[00598] Intermediate 62

Scheme 46

[00599] Intermediate 62a: benzyl 2-(4-methylpyrazol-1 -yl)acetate

[00600] Benzyl bromoacetate (0.17mL, 1 .1 mmol) was added to a flask containing fomepizole (0.07ml_, 0.91 mmol) and potassium carbonate (379mg, 2.74mmol) in MeCN (3ml_). The reaction mixture was heated to 60 °C and left to stir overnight. The reaction was then cooled to room temperature and quenched by the addition of water (20ml_) and extracted with EtOAc (3 x 20ml_). The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by column chromatography using an eluent of 0-10% EtOAc in heptane to give benzyl 2-(4-methylpyrazol-1 -yl)acetate (205mg, 0.89mmol, 97% yield) as a white solid.

Ή NMR (CDC , 400MHz) δ/ppm: 7.40- 7.33 (6H, m), 7.24 (1 H, s), 5.20 (2H, s), 4.89 (2H, s), 2.09 (3H, s). MS Method 2: RT: 1 .61 min, m/z 231 .2 [M+H] ⁺

[00601] Intermediate 62: 2-(4-methylpyrazol-1 -yl)acetic acid

[00602] Benzyl 2-(4-methylpyrazol-1 -yl)acetate (210mg, 0.91 mmol) was diluted in EtOAc (18ml_) and hydrogenated by passing through an H-cube reactor using a 10% Pd/C CatCart over a period of 1 hour. The reaction mixture was reduced in vacuo to afford 2-(4-methylpyrazol-1 -yl)acetic acid (1 10mg, 0.78mmol, 86% yield) as a white solid which was used in the next stage without further purification.

Ή NMR (CDCIs, 400MHz) δ/ppm: 7.40 (1 H, s), 7.23 (1 H, s), 4.92 (2H, s), 2.09 (3H, s) exchangeable proton not seen.

[00603] Intermediate 63

63a

diethyl

malonate,

NaH,

1 ,4-dioxane

63

Scheme 47

[00604] Intermediate 63a: 3-chloro-5-(trifluoromethyl)pyridazine

[00605] To a solution of 5-trifluoromethyl-2/-/-pyridizan-3-one (0.5g, 3.05mmol) in phosphorus oxychloride (2.5ml_, 26.82mmol) was added a drop of Ν,Ν-dimethylformamide. The mixture was heated to 120 °C for 2 hours. The reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was diluted with EtOAc (50ml_) and added to ice. The organics were separated and washed with water (50ml_), brine (50ml_), dried over Na2S04 and concentrated in vacuo. The residue was purified by column chromatography using an eluent of 50% EtOAc in heptane to give 3-chloro-5-(trifluoromethyl)pyridazine (84mg, 0.46mmol, 15% yield) as an orange liquid.

MS Method 2: RT: 1 .29 min, m/z 183.0 [M+H] ⁺

[00606] Intermediate 63b: diethyl 2-[5-(trifluoromethyl)pyridazin-3-yl]propanedioate [00607] To sodium hydride (328mg, 8.22mmol, 60% dispersion in mineral oil) in 1 ,4-dioxane (40ml_) at 0 °C was added diethyl malonate (0.94ml_, 6.16mmol) dropwise. The mixture was stirred for 30 minutes before adding a solution of 3-chloro-5-(trifluoromethyl)pyridazine (750mg,

4.1 1 mmol) in 1 ,4-dioxane (40ml_) dropwise. The reaction was allowed to warm to room temperature and stirred for 30 minutes before stirring at 120 °C overnight. The reaction was then cooled to room temperature and concentrated in vacuo and the residue dissolved in EtOAc (100ml_). The organic solution was washed with sat. aq. NaHC03 (2 x 50ml_) followed by sat. aq. NhUCI (2 x 50ml_). The organic layer was dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by column chormatography using an eluent 0-80% EtOAc and heptane to give diethyl 2-[5- (trifluoromethyl)pyridazin-3-yl]propanedioate (162mg, 0.53mmol, 13% yield) as an orange oil which crystalized on standing overnight.

MS Method 2: RT: 2.44 min, m/z 234.9 [M+H] ⁺

[00608] Intermediate 63: 2-[5-(trifluoromethyl)pyridazin-3-yl]acetic acid

[00609] To a solution of diethyl 2-[5-(trifluoromethyl)pyridazin-3-yl]propanedioate (162mg, 0.53mmol) in EtOH (5ml_) was added potassium fe/ -butoxide (89mg, 0.79mmol). The mixture was stirred at 60 °C overnight. The reaction mixture was cooled to room temperature and concentrated in vacuo to give 2-[5-(trifluoromethyl)pyridazin-3-yl]acetic acid (109mg, 0.53mmol, 100% yield) as a brown solid which was used in the next step without further purification.

MS Method 2: RT: 1 .02 min, m/z 206.9 [M+H] ⁺

[00610] Intermediate 64

H , 10% Palladium

64a 64

Scheme 48

[00611] Intermediate 64a: benzyl 2-[4-(trifluoromethyl)imidazol-1 -yl]acetate

[00612] Benzyl bromoacetate (0.14mL, 0.88mmol) was added to a flask containing potassium carbonate (305mg, 2.2mmol) and 4-(trifluoromethyl)-1 /-/-imidazole (100mg, 0.73mmol) in MeCN (3ml_). The reaction mixture was heated to 60 °C and left to stir overnight. The reaction was then quenched by the addition of water (20ml_) and extracted with EtOAc (3 x 20ml_). The combined organic layers were dried over Na2S04, filtered and reduced in vacuo to afford the product benzyl 2- [4-(trifluoromethyl)imidazol-1 -yl]acetate (194mg, 0.68mmol, 93% yield) as a yellow oil.

Ή NMR (CDCIs, 400MHz) δ/ppm: 7.55 (1 H, s), 7.41 - 7.30 (6H, m), 5.23 (2H, s), 4.75 (2H, s).

[00613] Intermediate 64: 2-[4-(trifluoromethyl)imidazol-1 -yl]acetic acid

[00614] Benzyl 2-[4-(trifluoromethyl)imidazol-1 -yl]acetate (210mg, 0.74mmol) was dissolved into EtOAc (14.8ml_) and hydrogenated by passing through an H-Cube reactor using a 10% Pd/C CatCart for 1 hour. The reaction mixture was then concentrated in vacuo to give 2-[4- (trifluoromethyl)imidazol-1 -yl]acetic acid (95mg, 0.48mmol, 66% yield) as a pale yellow solid which was used in the next step without further purification.

Ή NMR (CDCIs, 400MHz) δ/ppm: 7.82 (1 H, br s), 7.80-7.89 (1 H, m), 4.93 (2H, s) exhangable proton not seen.

MS Method 2: RT: 1 .01 min, m/z 195.0 [M+H] ⁺

[00615] Intermediate 65

LiOH,

65

Scheme 49

[00616] Intermediate 65a: ethyl 1 -methyl-5-(trifluoromethyl)pyrazole-4-carboxylate

[00617] Methylhydrazine (1 .2ml_, 22.79mmol) was slowly added to a mixture of cone. HCI

(1 .95ml_, 23.75mmol) and EtOH (1 .9ml_) at 0 °C and the mixture was stirred at this temperature for 30 minutes and then diluted with EtOH (7.7ml_). The resulting ethanolic solution of methylhydrazine hydrochloride was slowly added to a solution of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxo- butanoate (4.00ml_, 20.57mmol) in EtOH (58ml_) at 0 °C. The reaction was allowed to warm to room temperature and the mixture was stirred overnight. The light yellow solution was then concentrated in vacuo and the residue was suspended in water (20ml_), basified with sat. aq. Na2C03 (20ml_) and extracted with EtOAc (3 x 30ml_). The combined organic layers were washed with brine (30ml_), dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by by column chromatography using an eluent of 0-50% EtOAc in heptane to give ethyl 1 -methyl-5- (trifluoromethyl)pyrazole-4-carboxylate (2.91 g, 13.09mmol, 64% yield) as a colourless oil.

Ή NMR (CDCI3, 400MHz) δ/ppm: 7.93 (1 H, s), 4.34 (2H, q, J = 7.2Hz), 4.09 (3H, q, J = 1 .6Hz), 1 .37 (3H, t, J = 7.2Hz). ⁹ F NMR (CDCI3, 400MHz) δ/ppm: -57.1 .

MS Method 2: RT: 1 .62 min, m/z 223.0 [M+H] ⁺ [00618] Intermediate 65b: 1 -methyl-5-(trifluoromethyl)pyrazole-4-carboxylic acid

[00619] To a solution of ethyl 1 -methyl-5-(trifluoromethyl)pyrazole-4-carboxylate (2.91 g,

13.09mmol) in THF (52ml_) at 0 °C was added a solution of lithium hydroxide (627mg, 26.18mmol) in water (26ml_) and the mixture was stirred at room temperature overnight. The mixture was then acidified to pH 1 -2 with 1 M HCI and extracted with EtOAc (4 x 50ml_). The combined organic layers were washed with brine (50ml_), dried over Na2S04, filtered and concentrated in vacuo to give 1 - methyl-5-(trifluoromethyl)pyrazole-4-carboxylic acid (2.39g, 12.33mmol, 94% yield) as an off-white solid.

Ή NMR (CDC , 400MHz) δ/ppm: 8.02 (1 H, s), 4.13 (3H, q, J = 2.0Hz) exchangeable proton not seen. ⁹ F NMR (CDCb, 400MHz) δ/ppm: -57.2.

MS Method 2: RT: 1 .16 min, m/z 193.0 [M-H] ^"

[00620] Intermediate 65c: 2-(benzotriazol-1 -yl)-1 -[1 -methyl-5-(trifluoromethyl)pyrazol-4- yl]ethanone

[00621] To a stirred solution of 1 -methyl-5-(trifluoromethyl)pyrazole-4-carboxylic acid (2.39g, 12.33mmol) in dry toluene (49ml_) was added thionyl chloride (2.7ml_, 37.22mmol) dropwise at room temperature. The mixture was heated to reflux for 2 hours and then cooled to room temperature and concentrated in vacuo. The resulting oil (acid chloride) was dissolved in dry THF (70ml_) and 1 -[(trimethylsilyl)methyl]-1 /-/-benzotriazole (2.53g, 12.33mmol) was added. The mixture was heated to reflux overnight and then cooled to room temperature and concentrated in vacuo. The residual solid was taken up in THF (4ml_). The mixture was cooled to 0 °C, filtered and the solid washed with cold THF (2ml_) and dried in vacuo to afford 2-(benzotriazol-1 -yl)-1 -[1 -methyl-5- (trifluoromethyl)pyrazol-4-yl]ethanone (2.1 Og, 6.8mmol, 55% yield) as a white crystalline solid. Ή NMR (CDCI3, 400MHz) δ/ppm: 8.12 (1 H, dt, J = 8.4Hz, 0.9Hz), 8.05 (1 H, br s), 7.53 (1 H, dq, J = 6.9Hz, 0.9Hz), 7.46-7.39 (2H, m), 5.87 (2H, s), 4.13 (3H, q, J = 1 .8Hz). ⁹ F NMR (CDCb, 400MHz) δ/ppm: -57.7.

MS Method 2: RT: 1 .53 min, m/z 310.1 [M+H] ⁺

[00622] Intermediate 65d: [(Z)-2-(benzotriazol-1 -yl)-1 -[1 -methyl-5-(trifluoromethyl)pyrazol-4- yl]vinyl] trifluoromethanesulfonate

[00623] To a solution of 2-(benzotriazol-1 -yl)-1 -[1 -methyl-5-(trifluoromethyl)pyrazol-4-yl]ethanone (2.1 g, 6.79mmol) and 2,6-lutidine (1 .6ml_, 13.74mmol) in dry DCM (13.6ml_) at 0 °C was added tnfluoromethanesulfonic anhydride (1 .5ml_, 8.92mmol) dropwise. After 10 minutes, the ice bath was removed and the reaction mixture was stirred at room temperature overnight. The reaction was then diluted with EtOAc (50ml_) and sat. aq. NH4CI (30ml_) was added. The two layers were separated and the aqueous layer extracted with EtOAc (30ml_). The combined organic layers were washed with brine (30ml_), dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by column chromatography using an eluent of 0-100% EtOAc in heptane to afford [(Z)-2- (benzotriazol-1 -yl)-1 -[1 -methyl-5-(trifluoromethyl)pyrazol-4-yl]vinyl] trifluoromethanesulfonate (2.81 g , 6.34mmol, 94% yield) as a brown oil. Ή NMR (CDCI3, 400MHz) δ/ppm: 8.12 (1 H, dt, J = 8.4Hz, 0.8Hz), 7.84 (1 H, s), 7.69-7.64 (1 H, dq, J = 6.9Hz, 1 .OHz), 7.59 (1 H, dt, J = 8.3Hz, 0.9Hz), 7.52 (1 H, dq, J = 6.9Hz, 1 .OHz), 7.42 (1 H, s), 4.14 (3H, q, J = 1 .0Hz). ⁹ F NMR (CDCI3, 400MHz) δ/ppm: -58.6.

MS Method 2: RT: 1 .94 min, m/z 442.3 [M+H] ⁺

[00624] Intermediate 65e: methyl 2-[1 -methyl-5-(trifluoromethyl)pyrazol-4-yl]acetate

[00625] To a solution of [(Z)-2-(benzotriazol-1 -yl)-1 -[1 -methyl-5-(trifluoromethyl)pyrazol-4-yl]vinyl] trifluoromethanesulfonate (2.81 g, 6.37mmol) in acetonitrile (64mL) at 0 °C was added sodium methoxide (860mg, 15.93mmol) and the mixture was heated at 65 °C for 4 hours then cooled to room temperature and concentrated in vacuo. The residue was dissolved in MeOH (64ml_). Cone. HCI (1 .55ml_, 18.88mmol) was added and the mixture was heated at 70 °C overnight and then cooled to room temperature and concentrated in vacuo. The residue was dissolved in EtOAc (50ml_) and washed with sat. aq. NaHCC (50ml_), water (30ml_) and brine (50ml_), dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by column chromatography using an eluent of 0-100% EtOAc in heptane to give methyl 2-[1 -methyl-5-(trifluoromethyl)pyrazol-4- yl]acetate (208mg, 0.93mmol, 15% yield) as a yellow oil.

Ή NMR (CDCI3, 400MHz) δ/ppm: 7.54 (1 H, s), 4.00 (3H, d, J = 1 .2Hz), 3.73 (3H, s), 3.63 (2H, d, J = 1 .2Hz). ⁹ F NMR (CDCI3, 400MHz) δ/ppm: -58.6.

MS Method 3: RT: 4.57 min, m/z 223.2 [M+H] ⁺

[00626] Intermediate 65: 2-[1 -methyl-5-(trifluoromethyl)pyrazol-4-yl]acetic acid

[00627] To a solution of methyl 2-[1 -methyl-5-(trifluoromethyl)pyrazol-4-yl]acetate (200mg,

0.90mmol) in THF (3.6ml_) was added a solution of lithium hydroxide (43mg, 1 .8mmol) in water (1 .8ml_) and the mixture was stirred at room temperature for 2 hours. The mixture was acidified to pH 2-3 with 1 M HCI and extracted with EtOAc (3 x 10mL). The combined organic layers were washed with brine (10ml_), dried over Na2S04, filtered and concentrated in vacuo to give 2-[1 - methyl-5-(trifluoromethyl)pyrazol-4-yl]acetic acid (185mg, 0.89mmol, 99%) as an off-white solid which was used in the next step without further purification.

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 12.48 (1 H, br s), 7.52 (1 H, s), 3.94 (3H, d, J = 1 .2Hz), 3.57 (2H, d, J = 1 .2Hz) exchangeable proton not seen. ⁹ F NMR (CDCI3, 400MHz) δ/ppm: -57.6.

MS Method 3: RT: 3.68 min, m/z 209.1 [M+H] ⁺

[00628] Intermediate 66

66c

Scheme 50

[00629] Intermediate 66a: 2-(benzotriazol-1 -yl)-1 -[1 -(difluoromethyl)pyrazol-3-yl]ethanone

[00630] To a solution of 1 -(difluoromethyl)-1 H-pyrazole-3-carboxylic acid (1 .00g, 6.17mmol) in toluene (50ml_) was added thionyl chloride (1 .34ml_, 18.47mmol) dropwise at room temperature. The mixture was heated to reflux for 2 hours, and then cooled to room temperature and concentrated in vacuo. The mixture was taken up in THF (12.8ml_) and 1 -[(trimethylsilyl)methyl]-1 H- benzotriazole (1 .27g, 6.17mmol) was added and the resulting mixture was heated to reflux overnight. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by column chromatography using an eluent of 50% EtOAc and heptane to give 2-(benzotriazol-1 -yl)-1 -[1 -(difluoromethyl)pyrazol-3-yl]ethanone (776mg, 2.80mmol, 45% yield) as white crystals.

MS Method 3: RT: 4.69 min, m/z 278.1 [M+H] ⁺

[00631] Intermediate 66b: [(Z)-2-(benzotriazol-1 -yl)-1 -[1 -(difluoromethyl)pyrazol-3-yl]vinyl] trifluoromethanesulfonate

[00632] To a solution of 2-(benzotriazol-1 -yl)-1 -[1 -(difluoromethyl)pyrazol-3-yl]ethanone (776mg, 2.80mmol) and 2,6-lutidine (652μΙ_, 5.60mmol) in dry DCM (3ml_) at 0 °C was added

trifluoromethanesulfonic anhydride (621 μΙ_, 3.69mmol) dropwise. After 10 minutes, the ice bath was removed and the reaction mixture was stirred at room temperature overnight. The mixture was then washed with water (5ml_) and partitioned using a phase separator. The organic phase was concentrated in vacuo and the residue purified by column chromatography using an eluent of 20% EtOAc in heptane to give [(Z)-2-(benzotriazol-1 -yl)-1 -[1 -(difluoromethyl)pyrazol-3-yl]vinyl] trifluoromethanesulfonate (71 1 mg, 1 .74mmol, 62% yield) as a colourless oil.

MS Method 3: RT: 5.87 min, m/z 409.9 [M+H] ⁺

[00633] Intermediate 66c: methyl 2-[1 -(difluoromethyl)pyrazol-3-yl]acetate [00634] To a solution of [(Z)-2-(benzotriazol-1 -yl)-1 -[1 -(difluoromethyl)pyrazol-3-yl]vinyl] trifluoromethanesulfonate (71 1 mg, 1 .74mmol) in dry MeCN (1 OmL) at 0 °C was added sodium methoxide (188mg, 3.47mmol). After 10 minutes, the ice bath was removed and the reaction mixture was stirred at reflux for 2 hours. Sodium methoxide (188mg, 3.47mmol) was added and the reaction stirred for a further 2 hours. The reaction mixture was allowed to cool to room temperature. The residue was taken up in the minimum amount of EtOAc and the solids were filtered off and washed with EtOAc. The organic filtrate was concentrated in vacuo and taken up in MeCN (10ml_). The solution was cooled to 0 °C and a solution of sodium methoxide (0.31 mL, 3.47mmol) in MeOH (2ml_) was added dropwise. After 10 minutes, the ice bath was removed and the reaction mixture was stirred at reflux for 2 hours. The reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was taken up in MeOH (3ml_) and cone. HCI (0.64ml_, 7.82mmol) was added dropwise. The mixture was heated at reflux overnight. The mixture was cooled to room temperature and concentrated in vacuo and the residue purified by column chromatography using an eluent of 0-100% acetone in heptane to give methyl 2-[1 - (difluoromethyl)pyrazol-3-yl]acetate (191 mg, LOOmmol, 58% yield) as a colourless oil.

MS Method 3: RT: 3.95 min, m/z 191 .2 [M+H] ⁺

[00635] Intermediate 66: lithium 2-[1 -(difluoromethyl)pyrazol-3-yl]acetate

[00636] Methyl 2-[1 -(difluoromethyl)pyrazol-3-yl]acetate (0.19g, LOOmmol) was added to a solution of lithium hydroxide (48.1 1 mg, 2.01 mmol) in THF (3ml_) and the solution was stirred at room temperature overnight. The solution was concentrated in vacuo and the solid was washed with Et20. The organics were decanted and the solid was dried under vacuum to give lithium 2-[1 - (difluoromethyl)pyrazol-3-yl]acetate (177mg, LOOmmol, 100% yield) as a white powder which was used in the next step without further purification.

MS Method 3: RT: 3.95 min, m/z 171 .1 [M+H] ⁺

[00637] Intermediate 67

N ~ _c

HN-V

Scheme 51

[00638] Intermediate 67a: benzyl 2-[2-methyl-4-(trifluoromethyl)imidazol-1 -yl]acetate

[00639] Benzyl 2-bromoacetate (0.13ml_, 0.80mmol) was added to a stirring solution of 2-methyl- 4-(trifluoromethyl)-1 /-/-imidazole (100mg, 0.67mmol) and potassium carbonate (276mg,

2.00mmol) in MeCN (3ml_). The reaction mixture was heated to 60 °C and left to stir overnight. The reaction was then quenched by addition of water (20ml_) and extracted with EtOAc (3 x 20ml_). The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo to give benzyl 2-[2-methyl-4-(trifluoromethyl)imidazol-1 -yl]acetate (200mg, 0.67mmol, 100% yield) as a yellow oil which was used in the next step without further purification. MS Method 2: RT: 1 .78 min, m/z 299.1 [M+H] ⁺

[00640] Intermediate 67: 2-[2-methyl-4-(trifluoromethyl)imidazol-1 -yl]acetic acid

[00641] Benzyl 2-[2-methyl-4-(trifluoromethyl)imidazol-1 -yl]acetate (200mg, 0.67mmol) was dissolved in EtOAc (13.4ml_) and hydrogenated by passing through an H-Cube reactor using a 10% Pd/C CatCart for 1 hour. The reaction mixture was concentrated in vacuo to give 2-[2-methyl-4- (trifluoromethyl)imidazol-1 -yl]acetic acid (1 10mg, 0.53mmol, 79% yield) which was used in the next step without further purification.

Ή NMR (CDCb, 400MHz) δ/ppm: 7.74 (1 H, d, J = 1 .2Hz), 4.90 (2H, s), 2.29 (3H, s).

MS Method 2: RT: 2.88 min, m/z 209.1 [M+H] ⁺

[00642] Intermediate 68

Scheme 52

[00643] Intermediate 68: 2-[3-(trifluoromethyl)isoxazol-5-yl]acetic acid

[00644] n-Butyllithium (2.47M in n-heptane, 1 .2ml_, 2.96mmol) was added dropwise to a stirred solution of 5-methyl-3-(trifluoromethyl)isoxazole (407mg, 2.69mmol) and Ν,Ν,Ν,Ν- tetramethylethylenediamine (81 μΙ_, 0.54mmol) in THF (7ml_) at -78 °C under a nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 45 minutes and then C02(s) was added. The reaction mixture was allowed to warm to 0 °C and sat. aq. NH4CI (5ml_) was added followed by water (10ml_). The brown mixture was extracted with EtOAc (2 x 10ml_) and the combined organic extracts were discarded. The aqueous layer was acidified to pH 2-3 with 1 M HCI and extracted with EtOAc (3 x 15ml_). The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo to give 2-[3-(trifluoromethyl)isoxazol-5-yl]acetic acid (241 mg, 0.98mmol, 36% yield) as an off-white solid which was used in the next step without further purification.

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 13.20 (1 H, br s), 7.03 (1 H, s), 4.09 (2H, s). ⁹ F NMR (CDCb, 400MHz) δ/ppm: -62.3.

MS Method 2: RT: 1 .41 min, m/z 196.1 [M+H] ⁺

[00645] Intermediate 69

Scheme 53 [00646] Intermediate 69a: benzyl 2-indazol-1 -ylacetate

[00647] A mixture of benzyl bromoacetate (0.24ml_, 1 .51 mmol), indazole (0.15g, 1 .26mmol) and potassium carbonate (0.52g, 3.77mmol) in MeCN (3ml_) under a nitrogen atmosphere was stirred and heated to 60 °C overnight. The mixture was then allowed to cool to room temperature, quenched with water (20ml_) and extracted with EtOAc (3 x 20ml_). The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by column chromatography using an eluent of 0-20 % EtOAc in heptane to give benzyl 2-indazol-1 -ylacetate (0.23g, 0.87mmol, 69% yield) was isolated as a pale yellow solid.

Ή NMR (CDC , 400MHz) δ/ppm: 8.10 (1 H, d, J = 1 .0Hz), 8.01 (1 H, dt, J = 8.1 Hz, 1 .0Hz), 7.45-7.28 (7H, m), 7.23 (1 H, m), 5.24 (2H, s), 5.22 (2H, s).

MS Method 2: RT: 1 .82 min, m/z 267.1 [M+H] ⁺

[00648] Intermediate 69: 2-indazol-1 -ylacetic acid

[00649] Benzyl 2-indazol-1 -ylacetate (0.23g, 0.87mmol) was diluted in EtOAc (17.4ml_) and hydrogenated by passing through an H-Cube reactor using a 10% Pd/C CatCart for 2 hours. The reaction mixture was then concentrated in vacuo to give 2-indazol-1 -ylacetic acid (0.13g, 0.75mmol, 86% yield) as an off-white solid which was used in the next step without further purification.

MS Method 2: RT: 1 .20 min, m/z 177.1 [M+H] ⁺

[00650] Intermediate 70

70 70b

Scheme 54

[00651] Intermediate 70a: ethyl 2-[5-hydroxy-5-(trifluoromethyl)-4H-isoxazol-3-yl]acetate

[00652] Diisopropylamine (1 .4ml_, 9.99mmol) was slowly added at 0 °C to n-butyllithium solution in heptane (4.ml_, 9.88mmol) in THF (8.3ml_) and the mixture was stirred for 30 minutes, followed by the dropwise addition of ethyl acetoacetate (420μΙ_, 3.32mmol) and subsequent stirring at 0 °C for an additional 60 minutes. The mixture was then cooled to -78 °C, and ethyl difluoroacetate (370μΙ_, 3.7mmol) was slowly added. The temperature of the reaction mixture was allowed to warm to room temperature overnight. The mixture was cooled to 0 °C and 1 M HCI (30ml_) was added. The aqueous layer was extracted with DCM (3 x 20ml_). The combined organic layers were washed with brine (25ml_), dried over Na2S04, filtered and concentrated in vacuo. The resulting red oil was dissolved in acetic acid (8.3ml_) at 0 °C and hydroxylamine solution (250μΙ_, 4.08mmol, 50 wt% in H2O) was added. The cooling bath was removed and the solution was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was purified by flash column

chromatography using an eluent of 0-100% EtOAc in heptane to give ethyl 2-[5-(difluoromethyl)-5- hydroxy-4H-isoxazol-3-yl]acetate (423mg, 1 .89mmol, 57% yield) as a thick orange oil.

Regiochemistry confirmed by the ³ C NMR spectra in which a coupling was observed between the fluorine atoms and the sp3 hybridized carbon atom attached to the hydroxyl group (103.5 ppm, ² JC,F = 34 Hz).

MS Method 2: RT: 1 .31 min, m/z 222.1 [M-H] ^"

[00653] Intermediate 70b: ethyl 2-[5-(trifluoromethyl)isoxazol-3-yl]acetate

[00654] To a solution of ethyl 2-[5-(difluoromethyl)-5-hydroxy-4H-isoxazol-3-yl]acetate (408mg, 1 .83mmol) and Et3N (770μΙ_, 5.52mmol) in DCM (17ml_) at 0 °C was slowly added methanesulfonyl chloride (170μΙ_, 2.2mmol) and the mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by flash column chromatography using an eluent of 0-100% acetone in heptane to give ethyl 2-[5-(difluoromethyl)isoxazol-3-yl]acetate (295mg, 1 .44mmol, 79% yield) as a yellow oil.

MS Method 3: RT: 4.85 min, m/z 206.2 [M+H] ⁺

[00655] Intermediate 70: 2-[5-(difluoromethyl)isoxazol-3-yl]acetic acid

[00656] To a solution of ethyl 2-[5-(difluoromethyl)isoxazol-3-yl]acetate (285mg, 1 .39mmol) in THF (5.6ml_) was added lithium hydroxide (66mg, 2.78mmol) in water (2.8ml_) and the mixture was stirred at room temperature for 2 hours. The mixture was acidified to pH 2-3 with 1 M HCI and extracted with EtOAc (3 x 10ml_). The combined organic layers were washed with brine (10ml_), dried over Na2S04, filtered and concentrated in vacuo to give 2-[5-(difluoromethyl)isoxazol-3- yl]acetic acid (225mg, 1 .27mmol, 92% yield) as a tan solid.

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 12.86 (1 H, br s), 7.34 (1 H, t, J = 52.8Hz), 6.97 (1 H, t, J =

1 .6Hz), 3.81 (2H, s). ⁹ F NMR (DMSO-d6, 400MHz) δ/ppm: -1 17.9.

MS Method 2: RT: 1 .26 min, m/z 175.9 [M-H] ^"

[00657] Intermediate 71

Scheme 55

[00658] Intermediate 71a: ethyl 2-(3-isopropyl-1 ,2,4-oxadiazol-5-yl)acetate [00659] fe/ -Butyl ethyl malonate (1 .15ml_, 6.07mmol) and /V-Hydroxy-2-methylpropanimidamide (31 1 mg, 3.04mmol) were mixed and stirred at 130 °C for 2 hours. The mixture was then cooled to room temperature and the crude mixture was purified via column chromatography using an eluent of 0-100% acetone in heptane to afford ethyl 2-(3-isopropyl-1 ,2,4-oxadiazol-5-yl)acetate (273mg, 1 .38mmol, 45% yield) as a yellow oil.

Ή NMR (CDC , 400MHz) δ/ppm: 4.26 (2H, q, J = 7.2Hz), 3.97 (2H, s), 3.13 (1 H, sept, J = 7.2Hz), 1 .37 (6H, d, J = 7.2Hz), 1 .30 (3H, t, J = 7.2Hz).

MS Method 3: RT: 4.86 min, m/z 217.2 [M+H] ⁺

[00660] Intermediate 71 : 2-(3-isopropyl-1 ,2,4-oxadiazol-5-yl)acetic acid

[00661] To a solution of ethyl 2-(3-isopropyl-1 ,2,4-oxadiazol-5-yl)acetate (267mg, 1 .35mmol) in THF (5.4ml_) was added lithium hydroxide (64mg, 2.69mmol) in water (2.7ml_) and the mixture was stirred at room temperature for 2 hours. The mixture was then acidified to pH 1 -2 with 1 M HCI and this was extracted with EtOAc (3 x 10ml_). The combined organic layers were washed with brine (15ml_), dried over Na2S04, filtered and concentrated in vacuo to give 2-(3-isopropyl-1 ,2,4- oxadiazol-5-yl)acetic acid (213mg, 0.99mmol, 74%) as a thick yellow oil.

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 13.15 (1 H, br s), 4.10 (2H, s), 3.06 (1 H, sept, J = 6.9Hz), 1 .26 (6H, d, J = 6.9Hz).

MS Method 3: RT: 3.51 min, m/z 171 .1 [M+H] ⁺

[00662] Intermediate 72

72a 72

Scheme 56

[00663] Intermediate 72a: benzyl 2-(3-tert-butylpyrazol-1 -yl)acetate

[00664] A solution of 3-fe/?-butyl-1 /-/-pyrazole (100mg, 0.81 mmol) and potassium carbonate (334mg, 2.42mmol) in MeCN (3ml_) was left to stir for 30 minutes before the addition of benzyl bromoacetate (0.18ml_, 1 .21 mmol). The resultant mixture was heated to 60°C and left to stir at this temperature overnight. The reaction was then quenched on addition of water (20 mL) and extracted with EtOAc (3 x 20 mL). The organic fractions were combined, dried over Na2S04, filtered and reduced in vacuo. The residue was purified by column chromatography using an eluent of 0-10% EtOAc in heptane to give benzyl 2-(3-tert-butylpyrazol-1 -yl)acetate (150mg, 0.55mmol, 68% yield) as a colourless oil.

Ή NMR (CDCI3, 400MHz) δ/ppm: 7.41 -7.31 (6H, m), 6.20 (1 H, d, J = 2.3Hz), 5.21 (2H, s), 4.93 (2H, s), 1 .33 (9H, s).

MS Method 2: RT: 1 .93 min, m/z 273.1 [M+H] ⁺

[00665] Intermediate 72: 2-(4-methylpyrazol-1 -yl)acetic acid [00666] Benzyl 2-(3-tert-butylpyrazol-1 -yl)acetate (250mg, 0.92mmol) was dissolved in EtOAc (14.7ml_) and hydrogenated by passing through an H-cube reactor using a 10% Pd/C CatCart for 1 hour. The reaction mixture was then concentrated in vacuo to give the desired crude product. Ή NMR (DMSO-d6, 400MHz) δ/ppm: 7.56 (1 H, d, J = 2.3Hz), 6.13 (1 H, d, J = 2.3Hz), 4.86 (2H, s), 1 .23 (9H, s) exchangeable proton not seen.

MS Method 2: RT: 1 .36 min, m/z 183.1 [M+H] ⁺

[00667] Intermediate 73

73a 73b

Formic acid, Pd(PPh ₃ ) ₄ ,

73e 73d 73c

TFA

73

Scheme 57

[00668] Intermediate 73a: methyl 2,6-dichloro-5-fluoro-pyridine-3-carboxylate

[00669] Cone. HCI (0.75ml_, 1 1 .91 mmol) was slowly added to a stirring solution of 2,6-dichloro-5- fluoronicotinic acid (2.5g, 1 1 .91 mmol) in MeOH (15ml_). The reaction mixture was heated to 70 °C and left to stir for 2 hours. The reaction mixture was allowed to cool before being quenched by the addition of water (20ml_) and extracted with EtOAc (3 x 20ml_). The organic fractions were collected, dried (Na2S04), filtered and reduced in vacuo to afford the desired product methyl 2,6- dichloro-5-fluoro-pyridine-3-carboxylate (1 .80g, 8.03mmol, 67% yield) as a yellow solid.

MS Method 2: RT: 1 .69 min, 223.8m/z [M+H] ⁺

[00670] Intermediate 73b: methyl 2-chloro-5-fluoro-6-methoxy-pyridine-3-carboxylate

[00671] Sodium methoxide (1 .86ml_, 1 1 .91 mmol) was added to methyl 2,6-dichloro-5-fluoro- pyridine-3-carboxylate (1 .8g, 8.03mmol) in Methanol (9ml_) and the resultant mixture was left to stir for 1 hour. To the mixture was added EtOAc (20 ml_) and water (20 ml_), the layers were separated and the organics extracted using EtOAc (3 x 20 ml_). Organic fractions were collected, dried (Na2S04), filtered and reduced in vacuo to afford the desired product methyl 2-chloro-5-fluoro-6- methoxy-pyridine-3-carboxylate (1 .72g, 7.83mmol, 97% yield) as an orange solid.

Ή NMR (CDCb, 400MHz) δ/ppm: 7.92 (1 H, d, J = 9.6 Hz), 4.09 (3H, s), 3.92 (3H, s).

MS Method 2: RT: 1 .71 min, 220.0 m/z [M+H] ⁺

[00672] Intermediate 73c: methyl 5-fluoro-6-methoxy-pyridine-3-carboxylate

[00673] Triethylamine (1 .62ml_, 1 1 .61 mmol), tetrakis(triphenylphosphine)palladium(0) (0.45g, 0.39mmol) and formic acid (0.44ml_, 1 1 .61 mmol) were added to a flask containing a stirring solution of methyl 2-chloro-5-fluoro-6-methoxy-pyridine-3-carboxylate (1 .7g, 7.74mmol) in DMF (17ml_). The reaction mixture was then heated to 100 °C and left to stir for 4 hours. The reaction mixture was left to cool before being filtered through celite and the solvent removed in vacuo. The residue was taken up in EtOAc (50ml_), water (50ml_) added and the organics extracted with further EtOAc (3 x 50ml_). The organic layers were combined, dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by column chromatography using an eluent of 0-50% EtOAc in heptane) to afford the desired product methyl 5-fluoro-6-methoxy-pyridine-3-carboxylate (590mg, 3.19mmol, 41 % yield) as a white solid.

Ή NMR (CDC , 400MHz) δ/ppm: 8.61 (1 H, d, J = 1 .9Hz), 7.88 (1 H, dd, J = 10.4Hz, 1 .9Hz), 4.09 (3H, s), 3.92 (3H, s),

MS Method 3: RT: 5.10 min, 186.1 m/z [M+H] ⁺

[00674] Intermediate 73d: 5-fluoro-6-methoxy-pyridine-3-carboxylic acid

[00675] A solution of potassium hydroxide (885mg, 15.77mmol) and methyl 5-fluoro-6-methoxy- pyridine-3-carboxylate (730mg, 3.94mmol) in MeOH (15ml_) was stirred at room temperature overnight. The solvent was removed in vacuo and the residue taken up in water (20 ml_) and washed with ether (20ml_). The aqueous phase was acidified to pH 2 with 1 M HCI and extracted with EtOAc (3 x 20ml_). The organic fractions were collected, washed with brine, dried (Na2S04), filtered and reduced in vacuo to afford the desired product 5-fluoro-6-methoxy-pyridine-3-carboxylic acid (640mg, 3.74mmol, 95% yield) as a white solid.

Ή NMR (CDC , 400MHz) δ/ppm: 8.71 (1 H, d, J = 1 .9Hz), 7.95 (1 H, dd, J = 10.2Hz, 1 .9Hz), 4.14 (3H, s).

MS Method 2: RT: 1 .47 min, 171 .9 m/z [M+H] ⁺

Intermediate 73e: fert-butyl N-(5-fluoro-6-methoxy-3-pyridyl)carbamate

[00676] Using a blast shield and basic scrubber, diphenyl phosphoryl azide (376.91 uL, 1 .75mmol), Tert - butanol (207.99uL, 2.19mmol) and Triethylamine (244μΙ_, 1 .75mmol) were added to a stirring solution of 5-fluoro-6-methoxy-pyridine-3-carboxylic acid (250mg, 1 .46mmol) in Toluene (4ml_). The resultant yellow reaction mixture was heated to 1 10°C and left to stir at temperature for 3 hours. The reaction mixture was allowed to cool to room temperature before being quenched on addition of water (20 ml_) and extracted with EtOAc (3 x 20ml_). Organic fractions were collected, dried (Na2S04), filtered and reduced in vacuo. Crude material was purified by column chromatography (eluting in 0-50% EtOAc in heptane), affording the desired product tert-butyl N-(5-fluoro-6-methoxy- 3-pyridyl)carbamate (274mg,1 .13mmol, 77% yield) as a colourless oil.

MS Method 3: RT: 5.48 min, 243.2 m/z [M+H] ⁺

[00677] Intermediate 73: 5-fluoro-6-methoxy-pyridin-3-amine

[00678] fe/ -Butyl N-(5-fluoro-6-methoxy-3-pyridyl)carbamate (315mg, 1 .30mmol) was stirred in trifluoroacetic acid (1 .99ml_, 26.01 mmol) for 2 hours. The reaction mixture was reduced in vacuo and the residue taken up in water (100 mL) and 1 M HCI (100 mL) and extracted with EtOAc (50mL). To the aqueous layer was added solid sodium carbonate until a neutral/slightly basic pH was obtained. The aqueous was then further extracted with EtOAc (3 x 50mL), organic fractions collected, passed through phase separating filter paper and solvent reduced in vacuo to give 5- fluoro-6-methoxy-pyridin-3-amine (91 mg, 0.64mmol, 49% yield) as a dark red oil.

Ή NMR (CDC , 400MHz) δ/ppm: 7.45 (1 H, d, J = 2.5Hz), 6.85 (1 H, dd, J = 1 1 .3Hz, 2.5Hz), 3.97 (3H, s).

MS Method 2: RT: 0.91 min, 143.0 m/z [M+H] ⁺

[00679] Intermediate 74

Scheme 58

[00680] Intermediate 74a: Benzyl W-[4-bromo-2-(trifluoromethoxy)phenyl] carbamate [00681] Benzyl chloroformate (15.61 ml_, 109.37mmol) was added to a stirred solution of 4-bromo- 2-(trifluoromethoxy)aniline (1 1 .83ml_, 78.12mmol) and oxomagnesium (2.68g, 66.4mmol) in acetone (160ml_). The resulting solution was stirred overnight at room temperature. The mixture was stirred over the weekend at room temperature and then added to water (400ml_) and this was stirred for 2 hours at room temperature. The resulting solid was filtered off, washed with water and dried in vacuo. The solid was then stirred in EtOAc (300ml_) at 50 °C and the insoluble magnesium salts filtered off. The filtrate was concentrated in vacuo to give benzyl /V-[4-bromo-2- (trifluoromethoxy)phenyl]carbamate (28.27g, 72.65mmol, 93% yield) as a white solid which was used in the next step without further purification.

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 9.71 (1 H, s), 7.77 (1 H, d, J = 4.7Hz), 7.64 - 7.57 (2H, m), 7.44 - 7.30 (5H, m) and 5.76 (2H, s).

MS Method 2: RT: 2.10 min, m/z 389.9 [M+H] ⁺

[00682] Intermediate 74b: tert-Butyl W-[4-(benzyloxycarbonylamino)-3- (trifluoromethoxy)phenyl]carbamate

[00683] A solution of benzyl N-[4-bromo-2-(trifluoromethoxy)phenyl]carbamate (1 .00g, 2.56mmol), fe/ -butylcarbamat (0.45g, 3.84mmol), caesium carbonate (1 .67g, 5.13mmol) 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (0.15g, 0.26mmol) and

tris(dibenzylideneacetone)dipalladium(0) (0.12g, 0.13mmol) were dissolved in 1 ,4-dioxane (20mL) and the solution was then degassed and replaced with a nitrogen atmosphere. It was then heated to 100 °C for 5 hours. The solution was cooled to room temperature, diluted with EtOAc, filtered through celite and the filtrate concentrated in vacuo. The residue was purified by column chromatography using an eluent of 0-20% EtOAc in heptane to give fe/ -butyl Λ/-[4- (benzyloxycarbonylamino)-3-(trifluoromethoxy)phenyl]carbamat e (0.99g, 2.34mmol, 91 % yield) as a brown solid.

Ή NMR (CDC , 400MHz) δ/ppm: 8.09 (1 H, s), 7.57 (1 H, s), 7.46 - 7.35 (5H, m), 7.10 (1 H, dd, J = 9.0Hz, 1 .9Hz), 6.86 (1 H, s), 5.23 (2H, s) and 1 .53 (9H, s).

MS Method 2: RT: 2.00 min, m/z = 327 [M+H-Boc] ⁺

[00684] Intermediate 74c: benzyl W-[4-amino-2-(trifluoromethoxy)phenyl]carbamate

[00685] Trifluoroacetic acid (40ml_, 522.36mmol) was added to a stirred solution of fe/ -butyl Λ/-[4- (benzyloxycarbonylamino)-3-(trifluoromethoxy)phenyl]carbamat e (1 1 .00g, 25.8mmol) in DCM

(80ml_). The resulting mixture was stirred overnight at room temperature. The solution was then concentrated in vacuo and the residue dissolved in EtOAc (100ml_) and washed with sat. aq.

NaHC03 (1 OOmL). The aqueous layer was washed with further EtOAc (3 x 50ml_). The organic layers were combined, dried over Na2S04 and the solvent removed in vacuo. The residue was purified by column chromatography using an eluent of 10-100% EtOAc in heptane to give benzyl N-

[4-amino-2-(trifluoromethoxy)phenyl]carbamate (4.59g, 13.93mmol, 54% yield) as a brown solid.

Ή NMR (CD3OD, 400MHz) δ/ppm: 7.69 (1 H, d, J = 5.2Hz), 7.43 - 7.31 (5H, m), 7.01 - 6.97 (2H, m),

5.51 (1 H, s) and 5.21 (2H, s) exchangeable NH2 not seen.

MS Method 2: RT: 1 .65 min, m/z = 327 [M+H] ⁺ [00686] Intermediate 74d: benzyl W-[4-(cyanomethylamino)-2- (trifluoromethoxy)phenyl]carbamate

[00687] Bromoacetonitrile (1 .1 ml_, 15.47mmol) was added to a solution of benzyl /V-[4-amino-2- (trifluoromethoxy)phenyl]carbamate (4.59g, 14.06mmol) and Λ/,/V-diisopropylethylamine (2.94ml_, 16.87mmol) in THF (50ml_) and the resulting solution heated to 65 °C overnight. Further bromoacetonitrile was added and the mixture heated to 65 °C over the weekend. The mixture was then cooled to room temperature and solvent removed in vacuo. The residue was taken up in EtOAc (100ml_) and water (100ml_). The layers were separated and the aqueous extracted with further EtOAc (3 x 50ml_). The organic layers were combined, washed with sat. aq. NhUCI (100ml_), sat. aq. NaHC03 (100ml_), brine (100ml_), dried over Na2S04 and concentrated in vacuo. The residue was purified by column chromatography using an eluent of 10-20% EtOAc in heptane to give benzyl /V-[4-(cyanomethylamino)-2-(trifluoromethoxy)phenyl]carbamat e (1 .56g, 4.22mmol, 30% yield) as a brown solid.

Ή NMR (CDC , 400MHz) δ/ppm: 8.02 (1 H, br s), 7.42-7.38 (5H, m), 6.74 (1 H, s), 6.66 (1 H, dd, J = 8.8Hz, 2.8Hz), 6.61 (1 H, m), 5.22 (2H, s), 4.09 (2H, s) exchangeable NH not seen.

MS Method 2: RT: 1 .72 min, m/z = 365.9 [M+H] ⁺

[00688] Intermediate 74e: benzyl W-{4-[(2-cyanocyclopent-1 -en-1 -yl)(cyanomethyl)amino]-2- (trifluoromethoxy)phenyl}carbamate

[00689] p-Toluenesulfonic acid monohydrate (0.08g, 0.43mmol) was added to a solution of benzyl /V-[4-(cyanomethylamino)-2-(trifluoromethoxy)phenyl]carbamat e (1 .57g, 4.3mmol) and Intermediate 1 (0.52g, 4.73mmol) in toluene (40ml_). The resulting solution was heated to reflux for 5 hours under Dean-Stark conditions, the mixture was then cooled to room temperature and allowed to stand overnight. The solution was transferred to a separating funnel, washed with sat. aq. NaHCC solution (50ml_) and the aqueous washed with EtOAc (3 x 50ml_). The organic layers were combined, washed with brine (50ml_), dried over Na2S04 and the solvent removed in vacuo to give benzyl /V-{4-[(2-cyanocyclopent-1 -en-1 -yl)(cyanomethyl)amino]-2-

(trifluoromethoxy)phenyl}carbamate as a brown oil (2.02g, 4.3mmol, 100% yield) which was used as is in the next step without further purification.

MS Method 2: RT: 1 .90 min, m/z = 457.2 [M+H] ⁺

[00690] Intermediate 74f: benzyl W-[4-(3-amino-2-cyano-5,6-dihydro-4H-cyclopenta[£)]pyrrol- 1 -yl)-2-(trifluoromethoxy)phenyl]carbamate

[00691] Sodium fe/ -butoxide (0.43g, 4.42mmol) was added to a stirred solution of benzyl Λ/-[4-[(2- cyanocyclopenten-1 -yl)-(cyanomethyl)amino]-2-(trifluoromethoxy)phenyl]carbamat e (2.02g, 4.42mmol) in fe/ -butanol (30ml_). The resulting solution was heated to 80 °C for 3 hours. The reaction was cooled to room temperature and sat. NH4CI solution (100ml_) was added. The product was then extracted with EtOAc (4 x 40ml_). The organic layers were combined, washed with brine (100ml_), dried over Na2S04 and concentrated in vacuo to give benzyl /V-[4-(3-amino-2-cyano-5,6- dihydro-4/-/-cyclopenta[Jb]pyrrol-1 -yl)-2-(trifluoromethoxy)phenyl]carbamate as a brown oil (2.13g, 4.42mmol, 100% yield) which was used as is in the next step without further purification. MS Method 2: RT: 1 .94 min, m/z = 457 [M+H] ⁺

[00692] Intermediate 74g: benzyl W-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4- d]pyrimidin-5-yl)-2-(trifluoromethoxy)phenyl]carbamate

[00693] Formamidine acetate (1 .94g, 18.68mmol) was added to a stirred solution of benzyl Λ/-[4- (3-amino-2-cyano-5,6-dihydro-4H-cyclopenta[b]pyrrol-1-yl)-2- (trifluoromethoxy)phenyl]carbamate (2.13g, 4.67mmol) in EtOH (30ml_) and the solution heated to reflux for 3 hours. The solution was then cooled to room temperature, concentrated in vacuo and sat. aq. NaHC03 (100ml_) and EtOAc (50ml_) added to the residue. The layers were separated and the aqueous extracted with further EtOAc (2 x 50ml_). The organic layers were combined, washed with brine (100ml_), dried over Na2S04 and concentrated in vacuo to give benzyl /V-[4-(4-amino-7,8-dihydro-6/-/- cyclopenta[2,3]pyrrolo[2,4-d]pyrimidin-5-yl)-2-(trifluoromet hoxy)phenyl]carbamate as a brown oil (1 .48g, 3.05mmol, 65% yield) which was used as is in the next step without further purification. MS Method 2: RT: 1 .47 min, m/z = 484.1 [M+H] ⁺

[00694] Intermediate 74: 5-[4-amino-3-(trifluoromethoxy)phenyl]-7,8-dihydro-6H- cyclopenta[4,5]pyrrolo[1 ,2-d]pyrimidin-4-amine

[00695] Benzyl A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[4,5]pyrrolo[1 ,2-d]pyrimidin-5-yl)-2- (trifluoromethoxy)phenyl]carbamate (1 .48g, 3.05mmol) and palladium, 10 wt. % on carbon powder, dry (0.1 Og, 0.09mmol) in MeOH (30ml_) was stirred under an atmosphere of hydrogen over the weekend. The solution was then filtered through celite and concentrated in vacuo. The residue was purified by column chromatography using an eluent of 0-100% EtOAc in heptane, followed by 0- 20% MeOH in DCM to give 5-[4-amino-3-(trifluoromethoxy)phenyl]-7,8-dihydro-6/-/- cyclopenta[4,5]pyrrolo[1 ,2-d]pyrimidin-4-amine (448mg, 1 .28mmol, 42% yield) as a brown solid. Ή NMR (DMSO-d6, 400MHz) δ/ppm: 8.1 1 (1 H, s), 7.25 (1 H, s), 7.16 (1 H, dd, J = 8.6Hz, 2.4Hz), 6.92 (1 H, d, J = 8.6Hz), 5.78 (2H, br s), 5.52 (2H, br s), 2.78 (2H, t, J = 6.8Hz), 2.70 (2H, t, J = 6.8Hz), 2.44 (2H, q, J = 7.2Hz).

MS Method 2: RT: 1 .20 min, m/z = 350.1 [M+H] ⁺

[00696] Intermediate 75

Scheme 59

[00697] Intermediate 75a: fert-butyl W-[(fert-butoxy)carbonyl]-W-(2-chloro-4- nitrophenyl)carbamate

[00698] Di-fe/ -butyl dicarbonate (22.9g, 104.93mmol) was added to a stirred solution of 2-chloro- 4-nitro-aniline (8.63g, 50.01 mmol) and 4-dimethylamino pyridine, DMAP (0.3g, 2.46mmol) in THF (50ml_). The resulting solution was stirred over the weekend at room temperature. The solution was then concentrated in vacuo, and the residue dissolved in EtOAc (100ml_) and washed with 1 M citric acid solution (100ml_). The aqueous was extracted with further EtOAc (2 x 50ml_), and the combined organic layers washed with brine (100ml_), dried over Na2S04 and concentrated in vacuo to give fe/ -butyl /V-[(fe/ -butoxy)carbonyl]-/V-(2-chloro-4-nitrophenyl)carbamate (18.5g, 50.01 mmol, 100% yield) as an off-white solid which was used in the next step without further purification.

Ή NMR (CDC , 400MHz) δ/ppm: 8.34 (1 H, d, J = 2.4Hz), 8.16 (1 H, dd, J = 8.6Hz, 2.4Hz), 7.42 (1 H, d, J = 8.6Hz), 1 .42 (18H, s).

MS Method 2: RT: 2.06 min, m/z = 436 [M+Na+MeCN] ⁺ , 394 [M+Na] ⁺

[00699] Intermediate 75b: fert-butyl W-(4-amino-2-chlorophenyl)-W-[(iert- butoxy)carbonyl]carbamate

[00700] Iron (3.55g, 63.47mmol) and acetic acid (7.25ml_) were added to a solution of fe/ -butyl N- fe/?-butoxycarbonyl-N-(2-chloro-4-nitro-phenyl)carbamate (6.75g, 18.1 1 mmol) in MeOH (90ml_) and the mixture heated to reflux for 30 minutes. The solution was then cooled to room temperature and concentrated in vacuo. EtOAc (150ml_) and water (150ml_) were added and the mixture stirred for 15 minutes. The mixture was passed through celite to remove any insoluble material, the layers separated and the aqueous extracted with EtOAc (2 x 50ml_). The organic layers were combined, washed with sat. aq. NaHC03 (2 x 100ml_), brine (100ml_), dried over Na2S04 and concentrated in vacuo to give fe/ -butyl /V-(4-amino-2-chlorophenyl)-/V-[(fe/ -butoxy)carbonyl]carbamate (5.33g, 15.57mmol, 86% yield) as a yellow oil, which solidified on standing and was used in the next step without further purification.

Ή NMR (CD3OD, 400MHz): δ/ppm: 6.92 (1 H, d, J = 8.4Hz), 6.77 (1 H, d, J = 2.4Hz), 6.61 (1 H, dd, J = 8.4Hz, 2.4Hz), 1 .40 (18H, s) exchangeable NH ₂ not seen.

MS Method 2: RT: 1 .82 min, m/z = 343 [M+H] ⁺

[00701] Intermediate 75c: fert-butyl W-fert-butoxycarbonyl-W-[2-chloro-4- (cyanomethylamino)phenyl]carbamate

[00702] Bromoacetonitrile (1 .2ml_) was added to a solution of fe/ -butyl N-(4-amino-2-chloro- phenyl)-N-fe/?-butoxycarbonyl-carbamate (5.33g, 15.56mmol) and N,N-diisopropylethylamine (3.25ml_, 18.67mmol) in THF (85ml_). The solution was then heated to reflux for 40 hours. Further bromoacetonitrile (0.6ml_) in THF (2ml_) was added and the solution continued to be heated to reflux overnight. Further bromoacetonitrile (0.6ml_) was added and the mixture heated overnight. The reaction was then cooled to room temperature and concentrated in vacuo. Water (100ml_) and EtOAc (1 OOmL) were added to the residue and the organic layer separated. The aqueous was washed with further EtOAc (3 x 50mL). The organic layers were combined, washed with sat. aq. NH4CI solution (1 OOmL), sat. aq. NaHCOs solution (1 OOmL), brine (1 OOmL), dried over Na ₂ S0 ₄ and the concentrated in vacuo to give fe/ -butyl /V-fe/?-butoxycarbonyl-/V-[2-chloro-4- (cyanomethylamino)phenyl]carbamate (6.76g, 15.56mmol, 100% yield) as a brown oil which was used in the next step without further purification.

Ή NMR (CDCI3, 400 MHz) δ/ppm: 7.07 (1 H, d, J = 8.8Hz), 6.76 (1 H, dd, J = 3.2Hz), 6.58 (1 H, dd, J = 8.8Hz, 3.2Hz), 4.41 (1 H, t, J = 6.8Hz), 4.09 (2H, d, J = 6.8Hz), 1 .42 (18H, s).

MS Method 2: RT: 1 .84 min, m/z = 380.1 [M-H] ^"

[00703] Intermediate 75d: fert-butyl W-[2-chloro-4-[(2-cyanocyclopenten-1 -yl)- (cyanomethyl)amino]phenyl]carbamate

[00704] p-Toluenesulfonic acid monohydrate (0.34g, 1 .77mmol) was added to a stirred solution of fe/ -butyl N-fe/ -butoxycarbonyl-N-[2-chloro-4-(cyanomethylamino)phenyl]carba mate (6.76g,

17.7mmol) and Intermediate 1 (2.13g, 19.47mmol) in toluene (130mL). The resulting solution was then heated at reflux under Dean-Stark conditions for 6 hours. The solution was then cooled to room temperature and allowed to stand overnight. The solution was transferred to a separating funnel and the organic washed with sat. aq. NaHCC (1 OOmL). The aqueous was then washed with EtOAc (3 x 50mL). The organic layers were combined, washed with brine (100mL), dried over Na2S04 and concentrated in vacuo to give fe/ -butyl /V-[2-chloro-4-[(2-cyanocyclopenten-1 -yl)- (cyanomethyl)amino]phenyl]carbamate (5.33g, 14.33mmol, 81 % yield) as a brown oil which was used in the next step without further purification.

MS Method 2: RT: 1 .86 min, m/z = 371 .2 [M-H] ^" [00705] Intermediate 75e: fert-butyl N-[4-(3-amino-2-cyano-5,6-dihydro-4H- cyclopenta[b]pyrrol-1 -yl)-2-chloro-phenyl]carbamate

[00706] Potassium fe/ -butoxide (2.09g, 18.58mmol) was added to a solution of fe/ -butyl N-[2- chloro-4-[(2-cyanocyclopenten-1 -yl)-(cyanomethyl)amino]phenyl]carbamate (5.33g, 14.3mmol) in fe/ -butanol (55mL) and the solution heated to 80 °C for 3 hours. The solution was then cooled to room temperature and allowed to stand overnight. Sat. aq. NhUCI solution (100ml_) was added to the mixture and the product extracted with EtOAc (3 x 100ml_). The organic layers were combined, washed with brine (100ml_), dried over Na2S04 and concentrated in vacuo to give fe/ -butyl N-[4-(3- amino-2-cyano-5,6-dihydro-4/-/-cyclopenta[b]pyrrol-1 -yl)-2-chloro-phenyl]carbamate (3.34g, 9.01 mmol, 63% yield) a brown oil which was used in the next step without further purification.

MS Method 2: RT: 1 .96 min, m/z = 373.0 [M+H] ⁺

[00707] Intermediate 75f: fert-butyl N-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4- d]pyrimidin-5-yl)-2-chloro-phenyl]carbamate

[00708] Formamidine acetate (4.62g, 44.38mmol) was added to a stirred solution of fe/ -butyl N-[4- (3-amino-2-cyano-5,6-dihydro-4/-/-cyclopenta[b]pyrrol-1-yl)- 2-chloro-phenyl]carbamate (3.34g,

8.9mmol) in EtOH (40ml_). The resulting mixture was heated to 80 °C for 3 hours and then cooled to room temperature. The solution was then concentrated in vacuo and the residue partitioned between sat. aq. NaHC03 (100ml_) and EtOAc (100ml_). The layers were separated and the aqueous extracted with further EtOAc (3 x 50ml_). The organic layers were combined, washed with brine (100ml_), dried over Na2S04 and concentrated in vacuo to give fe/ -butyl N-[4-(4-amino-7,8- dihydro-6/-/-cyclopenta[2,3]pyrrolo[2,4-d]pyrimidin-5-yl)-2- chloro-phenyl]carbamate (3.12g,

7.74mmol, 87% yield) as a brown oil which was used in the next step without further purification. MS Method 2: RT: 1 .42 min, m/z = 401 .0 [M+H] ⁺

[00709] Intermediate 75: 5-(4-amino-3-chloro-phenyl)-7,8-dihydro-6H- cyclopenta[2,3]pyrrolo[2,4-d]pyrimidin-4-amine

[00710] te/ -Butyl N-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]py rimidin-5-yl)-2- chloro-phenyl]carbamate (3.12g, 7.8mmol) was dissolved in a solution of HCI (40ml_, 160mmol, 4M in dioxane) and the solution stirred overnight at room temperature. The solution was concentrated in vacuo. EtOAc (50ml_) and sat. NaHC03 solution (100ml_) were added to the residue and the layers separated. The aqueous was extracted with EtOAc (3 x 50ml_). The organic layers were combined, washed with brine (100ml_), dried over Na2S04 and concentrated in vacuo. The residue was purified by column chromatography using an eluent of 0-100% EtOAc in heptane, followed by 0-20% MeOH in DCM, to give 5-(4-amino-3-chloro-phenyl)-7,8-dihydro-6/-/-cyclopenta[2,3] pyrrolo[2,4-d]pyrimidin- 4-amine (0.472g, 1 .56mmol, 20% yield) as a brown glassy solid.

Ή NMR (CD3OD, 400MHz) δ/ppm: 8.13 (1 H, s), 7.36 (1 H, d, J = 2.4Hz), 7.14 (1 H, dd, J = 8.4Hz, 2.4Hz), 6.97 (1 H, d, J = 8.4Hz), 2.93-2.89 (2H, m), 2.77-2.75 (2H, m), 2.58-2.51 (2H, m) exchangeable protons not seen.

MS Method 2: RT: 1 .1 1 min, m/z = 300.8 [M+H] ⁺

[00711] Intermediate 76

Scheme 60

[00712] Intermediate 76a: tert-butyl N-[4-nitro-3-(trifluoromethyl)phenyl]carbamate

[00713] Di-fe/f-butyl dicarbonate (6.88g, 31 .54mmol) was added to a solution of 4-nitro-3- (trifluoromethyl)aniline (5.00g, 24.26mmol) and DMAP (0.39g, 3.15mmol) in THF (50mL) and the solution stirred overnight at room temperature. The mixture was added to brine (100ml_) and the product extracted with EtOAc (3 x 100ml_). The organic layers were combined, dried over Na2S04 and concentrated in vacuo to give fe/f-butyl N-[4-nitro-3-(trifluoromethyl)phenyl]carbamate (8.41 g, 24.26mmol, 100% yield) as an orange oil which was used in the next step without further purification.

MS Method 2: RT: 1 .93 min. m/z = 409.2 [M-H] ^"

[00714] Intermediate 76b: tert-butyl N-[4-amino-3-(trifluoromethyl)phenyl]carbamate

[00715] A solution of fe/f-butyl N-[4-nitro-3-(trifluoromethyl)phenyl]carbamate (8.41 g, 7.24mmol) and palladium, 10 wt. % on carbon powder, dry (1 .00g, 0.94mmol) in EtOAc (100ml_) was stirred under an atmosphere of hydrogen gas over the weekend. After this time further palladium, 10 wt. % on carbon powder, dry (1 .00g, 0.94mmol) was added and solution stirred overnight at room temperature under an atmosphere of hydrogen gas. The reaction was then filtered through celite and concentrated in vacuo to give fe/f-butyl N-[4-amino-3-(trifluoromethyl)phenyl]carbamate (7.40g, 7.24mmol, 100% yield) as a light orange oil which was used in the next step without further purification.

MS Method 2: RT: 1 .70 min., m/z = 277.1 [M+H] ⁺ [00716] Intermediate 76c: fert-butyl N-[4-(benzyloxycarbonylamino)-3- (trifluoromethyl)phenyl]carbamate

[00717] Benzyl chloroformate (2.76ml_, 19.33mmol) was added to a solution of fe/ -butyl N-[4- amino-3-(trifluoromethyl)phenyl]carbamate (6.93g, 18.41 mmol) in acetone (100ml_) and the resulting solution stirred over night at room temperature. The solid was filtered off, washed with acetone and the filtrate concentrated in vacuo. The residue was purified by column chromatography using an eluent of 0-100% EtOAc in heptane to give fe/ -butyl N-[4-(benzyloxycarbonylamino)-3- (trifluoromethyl)phenyl]carbamate as a yellow solid (6.17g, 15.10mmol, 82% yield).

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 7.99 (1 H, s), 7.78 (1 H, s), 7.47-7.34 (5H, m), 6.86 (1 H, s), 6.58 (1 H, s), 5.23 (1 H, s), 1 .54 (9H, s) exchangeable protons not seen.

MS Method 2: RT: 2.05 min, m/z = 409.2 [M-H] ^"

[00718] Intermediate 76d: benzyl W-[4-amino-2-(trifluoromethyl)phenyl]carbamate

[00719] Trifluoroacetic acid (50ml_, 652.96mmol) was added to a solution of fe/ -butyl N-[4- (benzyloxycarbonylamino)-3-(trifluoromethyl)phenyl]carbamate (6.76g, 16.48mmol) in DCM (50ml_) and the solution stirred overnight at room temperature. The reaction was concentrated in vacuo and the residue partitioned between DCM (100ml_) and sat. NaHC03 solution (150ml_). The layers were separated and the aqueous washed with DCM (3 x 10OmL). The organic layers were combined, dried over Na2S04 and concentrated in vacuo to give benzyl /V-[4-amino-2- (trifluoromethyl)phenyl]carbamate (5.1 1 g, 16.48mmol, 100% yield) as an orange gum which was used in the next step without further purification.

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 8.72 (1 H, s), 7.44-7.24 (5H, m), 7.01 (1 H, d, J = 8.8Hz), 6.87 (1 H, d, J = 2.4Hz), 6.78 (1 H, dd, J = 8.8Hz, 2.4Hz), 5.76 (2H, s), 5.08 (2H, s).

MS Method 2: RT: 1 .72 min, m/z = 31 1 .2 [M+H] ⁺

[00720] Intermediate 76e: benzyl N-[4-(cyanomethylamino)-2- (trifluoromethyl)phenyl]carbamate

[00721] Bromoacetonitrile (1 .37ml_, 19.7mmol) and Ν,Ν-diisopropylethylamine (3.84ml_,

21 .5mmol) were added to a stirred solution of benzyl N-[4-amino-2-

(trifluoromethyl)phenyl]carbamate (5.56g, 17.91 mmol) in THF (100ml_) and the resulting solution heated to reflux overnight. The mixture was then cooled to room temperature, concentrated in vacuo and the residue partitioned between EtOAc (50ml_) and brine (100ml_). The layers were separated and the aqueous layer extracted with further EtOAc (3 x 50ml_). The organic layers were combined, dried over Na2S04 and concentrated in vacuo to give benzyl N-[4-(cyanomethylamino)-2- (trifluoromethyl)phenyl]carbamate (5.96g, 17.19mmol, 100% yield) as a light brown solid which was used in the next step without further purification.

MS Method 2: RT: 1 .68 min, m/z = 348.0 [M-H] ^"

[00722] Intermediate 76f: benzyl N-[4-[(2-cyanocyclopenten-1 -yl)-(cyanomethyl)amino]-2- (trifluoromethyl)phenyl]carbamate [00723] A solution of benzyl N-[4-(cyanomethylamino)-2-(trifluoromethyl)phenyl]carbamate (7.66g, 21 .93mmol), Intermediate 1 (2.39g, 21 .93mmol) and p-toluenesulfonic acid monohydrate (0.42g, 2.19mmol) in toluene (100ml_) was stirred and heated to reflux under Dean-Stark conditions for 6 hours. The solution was then cooled to room temperature and concentrated in vacuo. The residue was partitioned between EtOAc (100ml_) and sat. aq. NaHC03 (150ml_). The layers were separated and the aqueous extracted with further EtOAc (3 x 50ml_). The organic layers were combined, dried over Na2S04 and concentrated in vacuo to give benzyl N-[4-[(2-cyanocyclopenten-1 -yl)- (cyanomethyl)amino]-2-(trifluoromethyl)phenyl]carbamate (9.65g, 21 .93mmol, 100% yield) as a brown oil which was used in the next step without further purification.

MS Method 2: RT: 1 .87 min, m/z = 441 .1 [M+H] ⁺

[00724] Intermediate 76g: benzyl N-[4-(3-amino-2-cyano-5,6-dihydro-4H-cyclopenta[b]pyrrol- 1 -yl)-2-(trifluoromethyl)phenyl]carbamate

[00725] Potassium fe/ -butoxide (1 .98g, 17.65mmol) was added to a stirred solution of benzyl N- [4-[(2-cyanocyclopenten-1 -yl)-(cyanomethyl)amino]-2-(trifluoromethyl)phenyl]carbamate (7.77g, 17.65mmol) in fe/ -butanol (100ml_) and the resulting solution was heated to reflux for 5 hours. The solution was then cooled to room temperature and the mixture added to sat. aq. NhUCI (100ml_). The product was extracted with EtOAc (4 x 100ml_). The organic layers were combined, washed with brine (100ml_), dried over Na2S04 and concentrated in vacuo to give benzyl N-[4-(3-amino-2- cyano-5,6-dihydro-4/-/-cyclopenta[b]pyrrol-1 -yl)-2-(trifluoromethyl)phenyl]carbamate (7.77g, 17.65mmol, 100% yield) as a dark brown oil which was used in the next step without further purification.

MS Method 2: RT: 1 .93 min, m/z = 441 .1 [M+H] ⁺

[00726] Intermediate 76h: benzyl N-[4-(5-amino-2,3-dihydro-1 H-cyclopenta[b]indol-4-yl)-2- (trifluoromethyl)phenyl]carbamate

[00727] Formamidine acetate (10.35g, 99.44mmol) was added to a solution of benzyl N-[4-(3- amino-2-cyano-5,6-dihydro-4/-/-cyclopenta[b]pyrrol-1 -yl)-2-(trifluoromethyl)phenyl]carbamate (10.95g, 24.86mmol) in EtOH (100ml_) and the resulting solution heated to reflux for 4 hours. The reaction was cooled to room temperature and concentrated in vacuo. The residue was partitioned between EtOAc (100ml_) and brine (100ml_). The layers were separated and the aqueous layer extracted with further EtOAc (3 x 10OmL), dried over Na2S04 and concentrated in vacuo to give benzyl N-[4-(5-amino-2,3-dihydro-1 /-/-cyclopenta[b]indol-4-yl)-2-(trifluoromethyl)phenyl]carba mate (1 1 .60g, 24.86mmol, 100% yield) as a brown oil which was used in the next step without further purification.

MS Method 2: RT: 1 .45 min, m/z = 468.2 [M+H] ⁺

[00728] Intermediate 76: 5-[4-amino-3-(trifluoromethyl)phenyl]-7,8-dihydro-6H- cyclopenta[2,3]pyrrolo[2,4-d]pyrimidin-4-amine

[00729] Palladium, 10 wt. % on carbon powder, dry (1 .00g, 0.94mmol) was added to a solution of benzyl N-[4-(4-amino-7,8-dihydro-6/-/-cyclopenta[2,3]pyrrolo[2,4-d] pyrimidin-5-yl)-2- (trifluoromethyl)phenyl]carbamate (6.74g, 14.43mmol) in MeOH (130ml_) and the resulting solution stirred under an atmosphere of hydrogen gas overnight. The solution was filtered through celite and concentrated in vacuo. The residue was purified by column chromatography using an eluent of 0- 100% EtOAc in heptane followed by 0-20% MeOH in DCM to give 5-[4-amino-3- (trifluoromethyl)phenyl]-7,8-dihydro-6/-/-cyclopenta[2,3]pyr rolo[2,4-d]pyrimidin-4-amine (1 .39g, 4.16mmol, 28% yield) as a brown solid.

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 8.1 1 (1 H, s), 7.37-7.35 (2H, m), 6.95 (1 H, d, J = 9.6Hz), 5.97 (2H, s), 5.52 (2H, s), 2.78 (2H, t, J = 6.8Hz), 2.70 (2H, t, J = 6.8Hz), 2.45 (2H, quintet, J = 6.8Hz). MS Method 2: RT: 1 .21 min, m/z = 334.1 [M+H] ⁺

[00730] Intermediate 77:

Scheme 61

[00731] Intermediate 77a: methyl 2-[4-[(4-cyano-2,5-dihydrofuran-3-yl)- (cyanomethyl)amino]phenyl]acetate

[00732] A solution of Intermediate 8b (15.00g, 73.45mmol), Intermediate 4 (12.24g,

1 10.17mmol) and p-toluenesulfonic acid monohydrate (1 .40g, 7.34mmol) in toluene (200ml_) was heated for 4 hours at 130 °C under Dean-Stark conditions. The reaction was allowed to cool to room temperature and concentrated in vacuo. EtOAc and sat. aq. NhUCI were added and the layers separated. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried over Na2S04, filtered concentrated in vacuo to give methyl 2-[4-[(4-cyano- 2,5-dihydrofuran-3-yl)-(cyanomethyl)amino]phenyl]acetate (15.14g, 30.55mmol, 42% yield) that was used without purification in the next step.

MS Method 2: RT: 1 .73min, m/z 298.1 [M+H] ⁺

[00733] Intermediate 77b: methyl 2-[4-(3-amino-2-cyano-4,6-dihydrofuro[3,4-b]pyrrol-1 - yl)phenyl]acetate [00734] A solution of methyl 2-[4-[(4-cyano-2,5-dihydrofuran-3-yl)- (cyanomethyl)amino]phenyl]acetate (15.00g, 50.45mmol) and sodium fe/ -butoxide (4.85g, 50.45mmol) in fe/f-butanol (100ml_) was heated at 80 °C for 1 hour. LCMS indicated conversion to product. The reaction mixture was allowed to cool to room temperature and sat. aq. NhUCI and EtOAc were added and the layers separated. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried over Na2S04, filtered and the solvent removed in vacuo to give methyl 2-[4-(3-amino-2-cyano-4,6-dihydrofuro[3,4-b]pyrrol-1 - yl)phenyl]acetate as a brown oil that was used directly in the next step without purification.

MS Method 2: RT: 1 .85min, m/z 298.1 [M+H] ⁺

[00735] Intermediate 77c: methyl 2-[4-(4-amino-6,8-dihydrofuro[4,5]pyrrolo[1 ,2-d]pyrimidin- 5-yl)phenyl]acetate

[00736] A solution of methyl 2-[4-(3-amino-2-cyano-4,6-dihydrofuro[3,4-b]pyrrol-1 - yl)phenyl]acetate (7.20g, 24.22mmol) and formamidine acetate (10.08g, 96.87mmol) in EtOH (150ml_) was heated at 80 °C for 2 hours. The reaction mixture was allowed to cool to room temperature and concentrated in vacuo. EtOAc and water were added and the layers separated. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by column chromatography using an eluent of 0-100% EtOAc in heptane followed by 0-20% MeOH in DCM) to give methyl 2-[4- (4-amino-6,8-dihydrofuro[4,5]pyrrolo[1 ,2-d]pyrimidin-5-yl)phenyl]acetate (1 .15g, 3.54mmol, 15% yield over 2 steps).

MS Method 2: RT: 0.86min, m/z 325.1 [M+H] ⁺

[00737] Intermediate 77: 2-[4-(4-amino-6,8-dihydrofuro[4,5]pyrrolo[1 ,2-d]pyrimidin-5- yl)phenyl]acetic acid

[00738] A solution of methyl 2-[4-(4-amino-6,8-dihydrofuro[4,5]pyrrolo[1 ,2-d]pyrimidin-5- yl)phenyl]acetate (1 .1 g, 3.39mmol) in EtOH (10ml_) and 1 M NaOH (10ml_) was stirred at room temperature for 3 hours. The EtOH was removed in vacuo and 1 M HCI (15ml_) was added and the mixture left to stand over the weekend. The precipitate was filtered and dried to give 2-[4-(4-amino- 6,8-dihydrofuro[4,5]pyrrolo[1 ,2-d]pyrimidin-5-yl)phenyl]acetate (1 .15g, 3.54mmol, 15% yield) which was used in the next step without further purification.

MS Method 2: RT: 0.78min, m/z 31 1 .1 [M+H] ⁺

[00739] Intermediate78:

Scheme 62

[00740] Intermediate 78a: methyl 2-[4-[(4-cyano-2,5-dihydrofuran-3-yl)-(cyanomethyl)amino]- 2-methoxy-phenyl]acetate

[00741] Intermediate 4 (9.49g, 85.38mmol) and p-toluenesulfonic acid monohydrate (0.74g, 4.27mmol) were added to a solution of Intermediate 9e (10.00g, 42.69mmol) in toluene (200mL) . The reaction mixture was refluxed for 5 hours under Dean-Stark conditions. Additional Intermediate 4 (9.49g, 85.38mmol) and p-toluenesulfonic acid monohydrate (0.74g, 4.27mmol) were added and the reaction heated overnight. The reaction mixture was then cooled to room temperature and concentrated in vacuo. DCM was added and the organic layer washed with sat. aq. NaHC03 and brine. The combined organic layers were dried over Na2S04 and solvent removed in vacuo to give methyl 2-[4-[(4-cyano-2,5-dihydrofuran-3-yl)-(cyanomethyl)amino]-2- methoxy-phenyl]acetate as a brown oil which was used directly in the next step without further purification.

MS Method 2: RT: 1 .47min, m/z 328.0 [M+H] ⁺

[00742] Intermediate 78b: 2-[4-(3-amino-2-cyano-4,6-dihydrofuro[3,4-b]pyrrol-1 -yl)-2- methoxy-phenyl]acetic acid

[00743] Sodium fe/ -butoxide (3.96g, 41 .24mmol) was added to a solution of methyl 2-[4-[(4- cyano-2,5-dihydrofuran-3-yl)-(cyanomethyl)amino]-2-methoxy-p henyl]acetate (13.5g, 41 .24mmol) in fe/ -butanol (100ml_). The reaction was stirred at 80 °C for 3 hours. The reaction was cooled to room temperature and solvent was removed in vacuo. Sat. aq. NhUCI and EtOAc were added to the crude residue. The organic layer was separated and the aqueous extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2S04 and concentrated under reduced pressure to yield 2-[4-(3-amino-2-cyano-4,6-dihydrofuro[3,4-b]pyrrol-1 -yl)-2-methoxy- phenyl]acetic acid (1 1 .70g, 37.50mmol, 91 % yield over 2 steps) which was used in the next step without further purification. MS Method 2: RT: 1 .22min, m/z 314.0 [M+H] ⁺

[00744] Intermediate 78: 2-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-d]pyrimidin-5- yl)-2- methoxy-phenyl]acetic acid

[00745] Formamidine acetate (8.64g, 82.98mmol) was added to a suspension of 2-[4-(3-amino-2- cyano-4,6-dihydrofuro[3,4-b]pyrrol-1 -yl)-2-methoxy-phenyl]acetic acid (6.50g, 20.75mmol) in EtOH (250ml_) and was stirred at 80 °C for 2 hours. The reaction mixture was concentrated in vacuo and the crude residue taken up in EtOAc and sat. aq. NaHC03, the biphasic mixture was separated. The aqueous layer was extracted with EtOAc. Both the organic and aqueous phases were concentrated in vacuo. Hot filtration of the aqueous residue in EtOAc was used to remove inorganics. The filtrate was passed through celite and solvent removed in vacuo. The residue was purified by reverse phase chromatography using an eluent of 15-40% water (0.01 % formic acid) in MeCN (0.01 % formic acid) to give 2-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-d]pyrimidin-5- yl)-2-methoxy- phenyl]acetic acid (327mg, 0.96mmol, 5% yield) as a brown solid.

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 8.19 (1 H, s), 7.35 (1 H, d, J = 7.9Hz), 7.08 (1 H, d, J = 2.1 Hz), 6.99 (1 H, dd, J =7.9Hz, 2.1 Hz), 5.79 (2H, br s), 5.07 (2H, t, J = 3.1 Hz), 4.99 (2H, t, J = 2.8Hz), 3.80 (3H, s), 3.49 (2H, s), exchangeable OH proton not seen.

MS Method 2: RT: 0.95min, m/z 341 .1 [M+H] ⁺

[00746] Intermediate 79

79 79b Scheme 63

[00747] Intermediate 79a: benzyl 2-(1 H-tetrazol-5-yl)acetate

[00748] A solution of benzyl cyanoacetate (1 .35ml_, 8.85mmol), sodium azide (604mg, 9.29mmol) and NH4CI (497mg, 9.29mmol) in DMF (8.9ml_) was heated at 100 °C overnight. The orange solution with some off-white precipitate was allowed to cool to room temperature and concentrated in vacuo. The residue was partitioned between water (10ml_) and EtOAc (10ml_). The two layers were separated and the aqueous layer was extracted with EtOAc (10ml_). The combined organic layers were washed with brine (2 x 10ml_), dried over Na2S04, filtered and concentrated in vacuo. The residue was purified via column chromatography using an eluent of 0-100% EtOAc in heptane to give benzyl 2-(1 H-tetrazol-5-yl)acetate (500mg, 2.29mmol, 26%) as a white solid. Ή NMR (DMSO-d6, 400MHz) δ/ppm: 7.40-7.33 (5H, m), 5.18 (2H, s), 4.26 (2H, s), exchangeable NH proton not seen).

MS Method 3: RT: 4.06 min, m/z 219.2 [M+H] ⁺ .

[00749] Intermediate 79b: benzyl 2-[5-(trifluoromethyl)-1 ,3,4-oxadiazol-2-yl]acetate

[00750] A solution of trifluoroacetic anhydride (400μΙ_, 2.88mmol) in DCM (1 ml_) was added dropwise to a suspension of benzyl 2-(1 H-tetrazol-5-yl)acetate (479mg, 2.2mmol) in DCM (2.6ml_) and the mixture was stirred at room temperature overnight. The mixture was then neutralized with sat. aq. NaHC03 (5ml_) and the aqueous layer was extracted with EtOAc (3 x 10ml_). The combined organic layers were washed with brine (15ml_), dried over Na2S04, filtered and concentrated in vacuo to give benzyl 2-[5-(trifluoromethyl)-1 ,3,4-oxadiazol-2-yl]acetate (610mg, 2.13mmol, 97%) as a yellow oil which was used in the next step without further purification.

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 7.40-7.37 (5H, m), 5.20 (2H, s), 4.94 (2H, s). ⁹ F NMR (DMSO-d6, 400MHz) δ/ppm: -64.6.

MS Method 3: RT: 5.68 min, m/z 287.1 [M+H] ⁺ .

[00751] Intermediate 79: 2-[5-(trifluoromethyl)-1 ,3,4-oxadiazol-2-yl]acetic acid

[00752] Benzyl 2-[5-(trifluoromethyl)-1 ,3,4-oxadiazol-2-yl]acetate (610mg, 2.13mmol) was dissolved in EtOAc (42.5ml_) and hydrogenated by passing through an H-cube reactor using a 10% Pd/C CatCart for 1 hour. The mixture was the concentrated in vacuo to give 2-[5-(trifluoromethyl)- 1 ,3,4-oxadiazol-2-yl]acetic acid (364mg, 1 .85mmol, 87%) as a thick oil.

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 13.35 (1 H, br s), 4.28 (2H, s). ⁹ F NMR (DMSO-d6, 400MHz) δ/ppm: -64.6.

MS Method 3: RT: 3.08 min, m/z 197.1 [M+H] ⁺ .

[00753] Intermediate 80

80a

KO'Bu

EtOH, H ₂ 0

80

Scheme 64

[00754] Intermediate 80a: benzyl 2-(3-isopropylpyrazol-1 -yl)acetate

[00755] 5-lsopropyl-1 H-pyrazole (100mg, 0.91 mmol) and potassium carbonate (376mg,

2.72mmol) was left to stir in MeCN (3ml_) for 30 mins before the addition of benzyl bromoacetate (0.21 ml_, 1 .36mmol). The resultant mixture was heated to 60 °C and left to stir at temperature overnight. The reaction was then quenched by addition of water (20ml_) and extracted with EtOAc (3 x 20 ml_). The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo to give benzyl 2-(3-isopropylpyrazol-1 -yl)acetate (200mg, 0.77mmol, 85%) which was used in the next step without further purification.

Ή NMR (CDCIs, 400MHz) δ/ppm: 7.41 -7.33 (6H, m), 6.18 (1 H, d, J = 2.3Hz), 5.21 (2H, s), 4.96 (2H, s), 3.04 (1 H, sept, J = 7.0Hz), 1 .31 (3H, s), 1 .29 (3H, s).

MS Method 2: RT: 1 .87 min, m/z 259.0 [M+H] ⁺

[00756] Intermediate 80: 2-(3-isopropylpyrazol-1 -yl)acetic acid

[00757] KO'Bu (98mg, 0.87mmol) was added to a stirred solution of benzyl 2-(3-isopropylpyrazol- 1 -yl)acetate (150mg, 0.58mmol) in EtOH (2ml_) and water (0.02ml_, 0.87mmol). The reaction mixture was left to stir for 2 hours at room temperature. The reaction was quenched by the addition of water (20ml_) and this was extracted using EtOAc (20ml_). The aqueous layer was acidified to pH 4 using 1 M HCI(aq) and extracted with EtOAc (3 x 20ml_). The combined organic layers were passed through phase separating filter paper and concentrated in vacuo to give 2-(3-isopropylpyrazol-1 - yl)acetic acid (46mg, 0.27mmol, 47% yield) as an orange oil which was used in the next step without further purification.

Ή NMR (CDCI3, 400MHz) δ/ppm: 7.29 (1 H, d, J = 2.3Hz), 6.18 (1 H, d, J = 2.3Hz), 4.92 (2H, s), 3.03 (1 H, sept, J = 7.0Hz), 2.12 (3H, d, J = 2.1 Hz), 2.07 (3H, d, J = 2.0Hz), exchangeable acid proton not seen.

MS Method 3: RT: 3.53 min, m/z 169.2 [M+H] ⁺

[00758] Intermediate 81

81 a

KO'Bu

EtOH/H ₂ 0

81

Scheme 65

[00759] Intermediate 81a: benzyl 2-(3-cyclopropylpyrazol-1 -yl)acetate

[00760] A suspension of 3-cyclopropyl-1 H-pyrazole (100mg, 0.92mmol) and potassium carbonate (383mg, 2.77mmol) in MeCN (3ml_) was left to stir at room temperature for 30 minutes before the addition of benzyl bromoacetate (0.21 mL, 1 .39mmol) and sodium iodide (139mg, 0.92mmol). The resulting mixture was heated to 60 °C and left to stir overnight. The reaction was quenched by the addition of water (20ml_) and extracted with EtOAc (3 x 20ml_). The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by column chromatography using an eluent of 0-20% EtOAc in heptane to give benzyl 2-(3-cyclopropylpyrazol- 1 -yl)acetate (204mg, 0.80mmol, 86% yield) as a colourless oil.

Ή NMR (CDCb, 400MHz) δ/ppm: 7.42-7.32 (6H, m), 5.98 (1 H, d, J = 2.3Hz), 5.21 (2H, s), 4.89 (2H, s), 1 .64 (1 H, tt, J = 8.3Hz, 5.0Hz), 0.97-0.88 (2H, m), 0.77-0.72 (2H, m).

MS Method 2: RT: 1 .88 min, m/z 257.0 [M+H] ⁺

Intermediate 81 : 2-(3-cyclopropylpyrazol-1 -yl)acetic acid

KO'Bu (151 mg, 1 .35mmol) was added to a flask containing benzyl 2-(3-cyclopropylpyrazol-1 - yl)acetate (230mg, 0.90mmol) in EtOH (2ml_) and water (0.02ml_, 1 .35mmol). The reaction mixture was left to stir for 2 hours. The reaction was then quenched by the addition of water (20ml_) and extracted using EtOAc (20ml_). The aqueous layer was acidified to pH 4 using 1 M HOI^ and extracted with EtOAc (3 x 20ml_). The combined organic layers were passed through a phase separating filter paper and concentrated in vacuo to give 2-(3-cyclopropylpyrazol-1 -yl)acetic acid (76mg, 0.46mmol, 51 % yield) as an off-white solid which was used in the next step without further purification.

Ή NMR (CDCb, 400MHz) δ/ppm: 7.33 (1 H, d, J = 2.3Hz), 5.98 (1 H, d, J = 2.4Hz), 4.90 (2H, s), 1 .98 (1 H, tt, J = 8.5Hz, 5.0Hz), 0.98 - 0.93 (2H, m), 0.77 - 0.70 (2H, m), exchangeable acid proton not seen.

MS Method 3: RT: 3.50 min, no mass ion seen.

[00761] Intermediate 82

82

Scheme 66

[00762] Intermediate 82a: benzyl 2-(4-tert-butylpyrazol-1 -yl)acetate

[00763] 4-(fe/?-butyl)-1 /-/-pyrazole (100mg, 0.81 mmol) and potassium carbonate (334mg, 2.42mmol) were left to stir in MeCN (3ml_) for 30 minutes before the addition of benzyl

bromoacetate (0.18ml_, 1 .21 mmol) and sodium iodide (121 mg, 0.81 mmol). The resultant mixture was heated to 60 °C and left to stir overnight. The reaction was then quenched by the addition of water (20ml_) and extracted with EtOAc (3 x 20ml_). the combined organic layers were dried over Na2S04, filtered and concentrated in vacuo to afford benzyl 2-(4-fe/?-butylpyrazol-1 -yl)acetate (105mg, 0.58mmol, 78% yield) a yellow oil which was used in the next step without further purification.

Ή NMR (CDCIs, 400MHz) δ/ppm: 7.42-7.32 (7H, m), 5.20 (2H, s), 4.92 (2H, s), 2.07 (9H, s).

MS method 2: RT: 1 .82 min, no mass ion seen.

[00764] Intermediate 82: 2-(4-tert-butylpyrazol-1 -yl)acetic acid

[00765] KO'Bu (124mg, 1 .1 mmol) was added to a flask containing benzyl 2-(4-tert-butylpyrazol-1 - yl)acetate (200mg, 0.73mmol) in EtOH (2ml_) and water (0.02mL, 1 .1 mmol). The reaction mixture was left to stir for 2 hours at room temperature. The reaction was then quenched by the addition of water (20ml_) and extracted with EtOAc (20ml_).The aqueous layer was acidified to pH 4 using 1 M HCI(aq) and extracted with EtOAc (3 x 20ml_). The combined organic layers were passed through a phase separating filter paper and concentrated in vacuo to give 2-(4-tert-butylpyrazol-1 -yl)acetic acid (105mg, 0.58mmol, 78% yield) as a brown sticky solid which was used in the next step without further purification.

Ή NMR (CDCb, 400MHz) δ/ppm: 7.50 (1 H, s), 7.27 (1 H, s), 4.94 (2H, s), 1 .28 (9H, s) exchangeable acid proton not seen.

MS Method 3: RT: 3.50 min, no mass ion seen.

[00766] Intermediate 83

LiOH,

THF/H ₂ 0

83

Scheme 67

[00767] Intermediate 83a: ethyl 2-(2-isopropyloxazol-4-yl)acetate

[00768] To a stirred solution of isobutyramide (1 .06ml_, 12.34mmol) in toluene (25ml_) and 1 ,4- dioxane (25ml_) was added ethyl 4-chloroacetoacetate (5ml_, 37mmol) and the mixture was heated to 120 °C overnight. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified via column chromatography using an eluent of 0-50% acetone in heptane to give ethyl 2-(2-isopropyloxazol-4-yl)acetate (71 1 mg, 2.92mmol, 24%) as a yellow oil.

Ή NMR (CDCIs, 400MHz) δ/ppm: 7.54 (1 H, t, J = 1 .2Hz), 4.20 (2H, q, J = 7.2Hz), 3.60 (2H, d, J = 1 .2Hz), 2.69 (1 H, sept, J = 7.2Hz), 1 .35 (6H, d, J = 7.2Hz), 1 .30 (3H, t, J = 7.2Hz).

MS Method 3: RT: 4.75 min, m/z 198.2 [M+H] ⁺

[00769] Intermediate 83: 2-(2-isopropyloxazol-4-yl)acetic acid [00770] To a solution of ethyl 2-(2-isopropyloxazol-4-yl)acetate (71 1 mg, 2.92mmol) in THF (1 1 .6ml_) was added a solution of LiOH (140mg, 5.84mmol) in water (5.8ml_) and the mixture was stirred at room temperature for 2 hours. The mixture was then acidified to pH 2-3 with 1 M HCI(aq) and extracted with EtOAc (3 x 10ml_). The combined organic layers were washed with brine (15ml_), dried over Na2S04, filtered and concentrated in vacuo to give 2-(2-isopropyloxazol-4-yl)acetic acid (494mg, 2.92mmol, 100%) as a yellow-orange solid.

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 12.39 (1 H, br s), 7.79 (1 H, t, J = 0.8Hz), 3.46 (2H, d, J = 0.8Hz), 3.03 (1 H, sept, J = 7.2Hz), 1 .25 (6H, d, J = 7.2Hz).

MS Method 3: RT: 3.51 min, m/z 170.2 [M+H] ⁺

[00771] Intermediate 84

84a fBuOH,

H ₂ S0 ₄ , TFA

O N ^ ^N \ / O N ^ ^N \ /

LiOH

N

THF/H ₂ 0

84 84b

Scheme 68

[00772] Intermediate 84a: ethyl 2-(1 H-tetrazol-5-yl)acetate

[00773] A stirred solution of ethyl cyanoacetate (0.94mL, 8.84mmol), sodium azide (603mg, 9.28mmol) and ammonium chloride (497mg, 9.28mmol) in DMF (8.9ml_) was heated at 100 °C overnight. The mixture was then allowed to cool to room temperature and the solvent was removed in vacuo. The residue was dissolved in water (4ml_) and acidified with 5M HCI(aq) then extracted with EtOAc (3 x 10ml_). The combined organic layers were washed with brine (15ml_), dried over Na2S04, filtered and concentrated in vacuo. The residue was dissolved in a small amount of EtOAc and heptane was added causing a solid to crash out. The mixture was filtered and the precipitate collected and dried to give ethyl 2-(1 H-tetrazol-5-yl)acetate (898mg, 5.74mmol, 65%) as a tan solid. Ή NMR (DMSO-d6, 400MHz) δ/ppm: 4.16 (2H, s), 4.15 (2H, q, J = 7.2Hz), 1 .21 (3H, t, J = 7.2Hz), exchangeable acid proton not seen.

MS Method 3: RT: 2.68 min, m/z 157.2 [M+H] ⁺ .

[00774] Intermediate 84b: ethyl 2-(2-fert-butyltetrazol-5-yl)acetate

[00775] To a solution of ethyl 2-(1 H-tetrazol-5-yl)acetate (488mg, 3.13mmol) in te/ -butanol (600μΙ_, 6.27mmol) and trifluoroacetic acid (1 .45ml_, 18.94mmol) was added sulfuric acid (86μΙ_, 1 .61 mmol) and the mixture was stirred at room temperature overnight. The mixture was then poured into ice-water (20ml_) and EtOAc (10ml_) was added. The mixture was passed through a phase separator and the aqueous layer was extracted with EtOAc (2 x 10ml_). The combined organic layers were washed with sat. aq. NaHC03 (10ml_) and brine (10ml_), dried over Na2S04, filtered and concentrated in vacuo to give ethyl 2-(2-tert-butyltetrazol-5-yl)acetate (282mg,

1 .32mmol, 42%) as a brown oil which was used in the next step without further purification.

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 4.13 (2H, q, J = 7.2Hz), 4.04 (2H, s), 1 .68 (9H, s), 1 .19 (3H, t, J = 7.2Hz).

MS Method 3: RT: 4.90 min, m/z 213.2 [M+H] ⁺

[00776] Intermediate 84: 2-(2-fert-butyltetrazol-5-yl)acetic acid

[00777] To a solution of ethyl 2-(2-fe/?-butyltetrazol-5-yl)acetate (275mg, 1 .29mmol) in THF (5.2ml_) was added a solution of LiOH (62mg, 2.59mmol) in water (2.6ml_) and the mixture was stirred at room temperature for 2 hours. The mixture was acidified to pH 2-3 with 1 M HCI(aq) and extracted with EtOAc (3 x 10ml_). The combined organic layers were washed with brine (15ml_), dried over Na2S04, filtered and concentrated in vacuo to give 2-(2-fe/?-butyltetrazol-5-yl)acetic acid (198mg, 1 .07mmol, 83%) as a light brown solid which was used in the next step without further purification.

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 12.77 (1 H, br s), 3.93 (2H, s), 1 .68 (9H, s).

MS Method 3: RT: 3.58 min, m/z 185.2 [M+H] ⁺ .

[00778] Intermediate 85

85

Scheme 69

[00779] Intermediate 85: 2,1 ,3-benzoxadiazol-5-amine

[00780] In a dry, nitrogen purged 5-10 mL microwave tube were successivelly introduced 5-bromo- 2,1 ,3-Benzoxadiazole (200mg, 1 .01 mmol), Pd ₂ (dba) ₃ (46mg, 0.05mmol) and tri-fe/f- butylphosphonium tetrafluoroborate (58mg, 0.20mmol) and toluene (1 ml_). The tube was evacuated/backfilled with nitrogen and then sealed. Lithium bis(trimethylsilyl)amide (1 .0 M in toluene, 2mL, 2mmol) was added and the reaction mixture was thermally heated at 50 °C overnight. After cooling to room temperature, the reaction mixture was diluted with ether (20mL) and the silylamide was deprotected by adding 2-3 drops of 1 M HCI(aq). The mixture was transferred to a separatory funnel and washed with sat. aq. NaHC03 (10mL). The organic layer was dried over Na2S04, filtered and concentrated in vacuo. The residue was purified via column chromatography using an eluent of 0-100% EtOAc in heptane. Three main fractions were collected containing the expected product and unprotected / partially deprotecetd silyl amide. The fractions were pooled, concentrated in vacuo and the residue dissolved in THF (1 mL). 1 M HCI(aq) (1 mL) was added and the mixture was stirred at room temperature for 1 hour. The mixture was made alkaline with 1 M NaOH(aq) and extracted with EtOAc (3 x 10mL). The combined organic layers were washed with brine (10ml_), dried over Na2S04 and concentrated in vacuo. The residue was purified via column chromatography using an eluent of 0-100% EtOAc in heptane to give 2,1 ,3-benzoxadiazol-5-amine (57mg, 0.42mmol, 42%) as a yellow-green solid.

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 7.76 (1 H, dd, J = 9.5Hz, 0.6Hz), 7.14 (1 H, dd, J = 9.5Hz, 1 .8Hz), 6.43 (2H, br s), 6.35 (1 H, dd, J = 1 .8Hz, 0.6Hz).

MS Method 2: RT: 1 .22 min, m/z 136.0 [M+H] ⁺

General Method A

Scheme 70

[00781] Example 1

[00782] N-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]py rimidin-5-yl)phenyl]-2- [4-chloro-3-(trifluoromethyl)phenyl]acetamide

[00783] Ν,Ν-Diisopropylethylamine (131 μΙ_, 0.75mmol) was added to a stirred solution of 5-(4- aminophenyl)-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]pyr imidin-4-amine (100mg, 0.38mmol), propylphosphonic anhydride (50%, wt in EtOAc, 336μΙ_, 0.57mmol) and 2-[4-chloro-3- (trifluoromethyl)phenyl]acetic acid (89mg, 0.38mmol) in THF (3ml_) and the solution was stirred at reflux for 12 hours. The solvent was removed in vacuo and the resulting residue was separated via SCX eluting with 2M Nhh in methanol. The solvent was removed in vacuo and the resulting solid was purified via column chromatography using an eluent of 0-15% MeOH in DCM and then purified via preparative LCMS. The collected fractions were separated via SCX eluting with 2M Nhh in MeOH. The solvents were removed in vacuo, yielding an oil to which DCM (1 ml_) and heptane (5ml_) were added causing a solid to crash out which was filtered and dried to give N-[4-(4-amino- 7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]pyrimidin-5-yl)p henyl]-2-[4-chloro-3- (trifluoromethyl)phenyl]acetamide (58mg, 0.12mmol, 32% yield) as a white powder.

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 10.49 (1 H, s), 8.13 (1 H, s), 7.87-7.85 (1 H, m), 7.65 (2H, d, J = 8.8Hz), 7.73-7.64 (2H, m), 7.39 (2H, d, J = 8.8Hz), 5.54 (2H, s), 3.84 (2H, s), 2.79 (2H, t, J = 7.2Hz), 2.73 (2H, t, J = 7.2Hz), 2.47-2.40 (2H, m).

MS Method 1 : RT: 3.52min, m/z 486.3 [M+H] ⁺

[00784] Example 2

[00785] N-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-d]pyrimidin-5- yl)-2-methoxy-phenyl]-2- [4-(trifluoromethoxy)phenyl]acetamide

[00786] DIPEA (0.12 ml, 0.87mmol) was added to a suspension of 5-(4-amino-3-methoxy-phenyl)- 6,8-dihydrofuro[2,3]pyrrolo[2,4-d]pyrimidin-4-amine (100mg, 0.35mmol), propylphosphonic anhydride (50%, wt in EtOAc, 0.32 ml_, 0.52mmol) and 4-(trifluoromethoxy)phenyl acetic acid (78mg, 0.35mmol) in THF (5ml_). The reaction mixture was stirred at reflux overnight. The reaction mixture was loaded directly onto a SCX cartridge, washed with methanol and the product eluted with 2M NH3. The basic eluent was combined and evaporated under vacuum to give a brown gum. The brown gum was purified by mass-directed preparative HPLC to give a colourless solid. The solid was washed through an SCX cartridge with 2M NH3 in methanol to give the free base N-[4-(4- amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-d]pyrimidin-5-yl)-2-me thoxy-phenyl]-2-[4-

(trifluoromethoxy)phenyl]acetamide as a colourless solid (27mg, 0.05mmol, 15% yield).

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 9.55 (1 H, br s), 8.18 (1 H, br s), 8.14 (1 H, br s), 7.49 (2H, d, J = 9.0Hz), 7.34 (2H, d, J = 9.0Hz), 7.18 (1 H, d, J = 3.0Hz), 7.00 (1 H, dd, J = 9.0Hz, 3.0Hz), 5.86 (2H, br s), 5.06 (2H, t, J = 3.0Hz), 4.95 (2H, t, J = 3.0Hz), 3.89 (3H, s), 3.85 (2H, s).

MS Method 1 : RT: 3.19 min, m/z 500.3 [M+H] ⁺

[00787] Example 3

[00788] N-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]py rimidin-5-yl)-2- methoxy-phenyl]-2-[6-(trifluoromethyl)pyridazin-3-yl]acetami de

[00789] A stirred solution of 5-(4-amino-3-methoxy-phenyl)-7,8-dihydro-6H- cyclopenta[2,3]pyrrolo[2,4-d]pyrimidin-4-amine (150mg, 0.51 mmol) , [2-[6-(trifluoromethyl)pyridazin- 3-yl]acetyl]oxylithium (107mg, 0.51 mmol) and N,N-diisopropylethylamine (221 μΙ_, 1 .27mmol) in THF (3ml_) was heated to reflux. After 5 minutes propylphosphonic anhydride (453μΙ_, 0.76mmol) was added and the reaction left for 16 hours. The reaction mixture was separated via SCX eluting with 2M NH3 in methanol. The solute was purified via reverse phase column chromatography using an eluent of 0-50% MeCN+0.1 % formic acid in H2O+0.1 % formic acid, with collected fractions pooled, passed through SCX (5g isolute cartridge) eluting with 2 M NH3 in MeOH and concentrated in vacuo to yield N-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]py rimidin-5-yl)-2-methoxy- phenyl]-2-[6-(trifluoromethyl)pyridazin-3-yl]acetamide (27mg, 0.06mmol, 1 1 % yield) as a white solid. Ή NMR (DMSO-d6, 400MHz) δ/ppm: 9.88 (1 H, s), 8.28 (1 H, d, J = 9.0Hz), 8.13 (2H, d, J = 8.1 Hz), 8.06 (1 H, d, J = 9.0Hz), 7.16 (1 H, d, J = 2.4Hz), 6.98 (1 H, dd, J = 8.1 Hz, 2.4Hz), 5.61 (2H, s), 4.41 (2H, s), 3.92 (3H, s), 2.83-2.76 (4H, m), 2.49-2.41 (2H, m).

MS Method 1 : RT: 2.84 min, m/z 484.3 [M+H] ⁺

[00790] The compounds shown in the table below were similarly prepared by varying the amine and acid shown in the reaction scheme for General Method A using amine intermediates, 2, 3, 5, 6, 7, 10, 73, 74 and 76 and acid intermediates 13 to 32 and 37, 38, 39, 43, 46, 49, 51 , 52, 53, 54, 55, 57, 58, 59, 60, 61 , 62, 64, 65, 67, 68, 69, 70, 71 , 72, 73, 79, 80, 81 , 82, 83 and 84 as well as commerciall available acids:

[00791] Example 4

[00792] General Method B

Scheme 71

[00793] N-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]py rimidin-5-yl)p

fluoro-5-(trifluoromethyl)phenyl]acetamide

[00794] BOP (274mg, 0.62mmol) was added to a stirred solution of 2-fluoro-5- (trifluoromethyl)phenylacetic acid (69mg, 0.31 mmol) and Ν,Ν-diisopropylethylamine (108μΙ_, 0.62mmol) in DMF (2mL) and the reaction stirred for 20 minutes. 5-(4-aminophenyl)-7,8-dihydro-6H- cyclopenta[2,3]pyrrolo[2,4-d]pyrimidin-4-amine (82mg, 0.31 mmol) was added and the reaction stirred overnight at 60 °C. The reaction mixture was partitioned between water (20ml_) and EtOAc (20ml_) and the aqueous layer extracted with EtOAc (2x20ml_). The combined organic fractions were washed with brine (4x40ml_). The organic fraction was dried over Na2S04, the solvent removed in vacuo and the residue was purified via preparative LCMS to yield N-[4-(4-amino-7,8- dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]pyrimidin-5-yl)pheny l]-2-[2-fluoro-5- (trifluoromethyl)phenyl]acetamide (62mg, 0.13mmol, 42% yield) as a yellow solid.

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 10.54 (1 H, s), 8.14 (1 H, s), 7.88 (1 H, dd, J = 6.6Hz, 1 .8Hz), 7.78-7.74 (3H, m), 7.46 (1 H, t, J = 9.0Hz), 7.39 (2H, d, J = 8.8Hz), 5.57 (2H, s), 3.91 (2H, s), 2.79 (2H, t, J = 7.0Hz), 2.74 (2H, t, J = 7.4Hz), 2.43 (2H, app p, J = 7.0Hz).

MS Method 1 : RT: 3.36 min, m/z 470.3 [M+H] ⁺

[00795] The compounds shown in the table below were similarly prepared by varying the amine and acid shown in the reaction scheme for General Method B using amine Intermediates 2, 3 and 5 and acid Intermediates 60, 63 and 66 as well as commercially available acids:

Compound Compound Name Mass spec NMR

[00796] Example 5

[00797] General Method C

Scheme 72

[00798] N-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]py rimidin-5-yl)phenyl]-2- (3,5-dimethoxyphenyl)acetamide

[00799] 5-(4-aminophenyl)-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4- d]pyrimidin (90mg, 0.34mmol) was added to a stirred solution of (3,5-dimethoxyphenyl)acetic acid (0.06ml_, 0.34mmol) and 1 -hydroxybenzotriazole hydrate (77mg, 0.51 mmol) in DMF (2mL) and the solution was stirred overnight. The reaction was partitioned between water (20ml_) and EtOAc (20ml_), the organic layer was washed with brine (3 x 30ml_), dried over Na2S04 and the solvents removed in vacuo. The resulting residue was purified via preparative LCMS to yield N-[4-(4-amino-7,8-dihydro-6H- cyclopenta[2,3]pyrrolo[2,4-d]pyrimidin-5-yl)phenyl]-2-(3,5-d imethoxyphenyl)acetamide (22mg, 0.05mmol, 15% yield) as a colourless powder.

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 10.39 (1 H, s), 8.16 (1 H, s), 7.77 (2H, d, J = 8.8Hz), 7.38 (2H, d, J = 8.8Hz), 6.53 (2H, s), 6.41 (1 H, s), 5.73 (2H, s), 3.74 (6H, s), 3.60 (2H, s), 2.80 (2H, t, J = 6.9Hz), 2.75-2.71 (2H, m), 2.49 (2H, m).

MS Method 1 : RT: 2.99 min, m/z 444.3 [M+H] ⁺

[00800] The compounds shown in the table below were similarly prepared by varying the amine and acid shown in the reaction scheme for General Method C using amine Intermediates 1 and 2 and commercially available acids:

Compound Compound Name Mass spec NMR

[00801] Example 6

[00802] General Method D

Scheme 73

[00803] 2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[4,5]pyrrolo[1 ,2-d]pyrimidin-5-yl)phenyl]-N- (1 -methylindol-5-yl)acetamide

[00804] To a solution of 2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[4,5]pyrrolo[1 ,2-d]pyrimidin-5- yl)phenyl]acetic acid (50mg, 0.16mmol), 5-Amino-1 -N-methylindole (23mg, 0.16mmol) and propylphosphonic anhydride (0.07ml_, 0.24mmol) in THF (5ml_) was added N,N- diisopropylethylamine (0.06ml_, 0.32mmol) and the resulting mixture was stirred at reflux overnight. LCMS showed conversion to product. The solvent was removed in vacuo and the crude residue was passed through an SCX cartridge, eluting first with methanol and then with 7N

ammonia/methanol solution. The ammonia solution was removed in vacuo and the residue was purified by column chromatography (0-10% MeOH/DCM) to afford 2-[4-(4-amino-7,8-dihydro-6H- cyclopenta[4,5]pyrrolo[1 ,2-d]pyrimidin-5-yl)phenyl]-N-(1-methylindol-5-yl)acetamide (20mg, 0.046mmol, 28% yield).

[00805] Ή NMR (DMSO-d6, 400MHz) δ/ppm: 10.05 (1 H, s), 8.15 (1 H, s), 7.9 (1 H, d, J = 1 .5Hz), 7.54 (2H, d, J = 8.5Hz), 7.42 (2H, d, J = 8.2Hz), 7.37 (1 H, d, J = 8.3Hz), 7.29 (2H, dd, J = 7.0Hz, 3.0Hz), 6.36 (1 H, dd, J = 3.2Hz, 0.8Hz), 5.55 (2H, bs), 3.76 (3H, s), 3.75 (2H, s), 2.83-2.74 (4H, m), 2.50 (2H, m, under DMSO).

MS Method 1 : RT: 2.86min, m/z 437.4 [M+H] ⁺

[00806] The compounds shown in the table below were similarly prepared by varying the amine and acid shown in the reaction scheme for General Method D, using acid Intermediates 8, 9, 78 and 79 and amine Intermediates 35, 41 , 42, 44, 45, 47, 48, 50, 72 and 85 as well as commercially available amines:

Compound Compound Name Mass spec NMR

2-[4-(4-amino-7,8- MS Method 1 : Ή NMR: (DMSO-d6, 400MHz)

IXX dihydro-6H- RT: 2.96 min, δ/ppm: 9.94 (1 H, s), 8.15 (1 H, cyclopenta[2,3]pyrrol m/z 416.4 s), 7.73 (1 H, d, J = 6.8Hz), o[2,4-d]pyrimidin-5- [M+H] ⁺ 7.52 (2H, d, J = 8.1 Hz), 7.42 yl)phenyl]-N-(2- (2H, d, J = 8.1 Hz), 7.13 (1 H, fluoro-5-methyl- dd, J = 1 1 .0Hz, 8.5Hz), 6.98- phenyl)acetamide 6.92 (1 H, m), 5.52 (2H, br s),

3.84 (2H, s), 2.84-2.73 (4H, m), 2.50 (2H, m), 2.26 (3H, s).

H ₂ N I 2-[4-(4-amino-7,8- MS Method 1 : Ή NMR: (DMSO-d6, 400MHz)

_ΗΝ dihydro-6H- RT: 3.43 min, δ/ppm: 10.76 (1 H, s), 8.2 (1 H, cyclopenta[2,3]pyrrol m/z 487.0 d, J = 2.5Hz), 8.14 (1 H, s), o[2,4-d]pyrimidin-5- [M+H] ⁺ 7.87 (1 H, dd, J = 8.8Hz, yl)phenyl]-N-[4- 2.5Hz), 7.68 (1 H, d, J = chloro-3- 8.6Hz), 7.52 (2H, d, J =

(trif 1 u o ro methyl) p h e n 8.5Hz), 7.42 (2H, d, J = yl]acetamide 8.3Hz), 5.52 (2H, br s), 3.8

Η ₂ Ν 1 (2H, s), 2.84-2.72 (4H, m),

2.50 (2H, m).

2-[4-(4-amino-7,8- MS Method 1 : Ή NMR: (DMSO-d6, 400MHz) dihydro-6H- RT: 2.96 min, δ/ppm: 8.59 (1 H, t, J = 5.5Hz), cyclopenta[2,3]pyrrol m/z 398.4 8.15 (1 H, s), 7.47 (2H, d, J = o[2,4-d]pyrimidin-5- [M+H] ⁺ 8.5Hz), 7.39 (2H, d, J = yl)phenyl]-N-benzyl- 8.4Hz), 7.35-7.29 (2H, m), acetamide 7.27-7.22 (3H, m), 5.53 (2H, br s), 4.30 (2H, d, J = 6.0Hz),

Η ₂ Ν Τ 3.60 (2H, s), 2.83-2.73 (4H, m), 2.50 (2H, m).

2-[4-(4-amino-7,8- MS Method 1 : Ή NMR: (DMSO-d6, 400MHz) dihydro-6H- RT: 2.79 min, δ/ppm: 9.81 (1 H, s), 8.14 (1 H, cyclopenta[2,3]pyrrol m/z 432.3 s), 7.63 (1 H, t, J = 8.9Hz), 7.52 o[2,4-d]pyrimidin-5- [M+H] ⁺ (2H, d, J = 8.4Hz), 7.41 (2H, d, yl)phenyl]-N-(2- J = 8.4Hz), 6.91 (1 H, dd, J = fluoro-4-methoxy- 12.7Hz, 2.5Hz), 6.68 (1 H, ddd, phenyl)acetamide J = 8.9Hz, 2.7Hz, 1 .2Hz), 5.52

(2H, br s), 3.79 (2H, s), 3.75

Η ₂ Ν 1 (3H, s), 2.83-2.73 (4H, m),

2.50 (2H, m).

2-[4-(4-amino-7,8- MS Method 1 : Ή NMR (DMSO-d6, 400MHz) dihydro-6H- RT: 2.55 min, δ/ppm: 10.24 (1 H, s), 8.38 (1 H, cyclopenta[2,3]pyrrol m/z 415.2 d, J = 2.6Hz), 8.16 (1 H, s), o[2,4-d]pyrimidin-5- [M+H] ⁺ 7.93 (1 H, dd, J = 8.9Hz, yl)phenyl]-N-(6- 2.7Hz), 7.52 (2H, d, J = methoxy-3- 8.5Hz), 7.41 (2H, d, J = pyridyl)acetamide 8.5Hz), 6.80 (1 H, d, J =

8.9Hz), 5.57 (2H, br s), 3.82

Η ₂ Ν 1 (3H, s), 3.76 (2H, s), 2.83-2.73

(4H, m), 2.50 (2H, m).

2-[4-(4-amino-7,8- MS Method 1 : Ή NMR (DMSO-d6, 400MHz) dihydro-6H- RT: 3.07 min, δ/ppm: 1 1 .28 (1 H, s), 8.77- cyclopenta[2,3]pyrrol m/z 453.3 8.72 (1 H, m), 8.29 (1 H, d, J = o[2,4-d]pyrimidin-5- [M+H] ⁺ 8.5Hz), 8.18 (1 H, dd, J = yl)phenyl]-N-[5- 8.8Hz, 2.6Hz), 8.15 (1 H, s),

(trifluoromethyl)-2- 7.54 (2H, d, J = 8.4Hz), 7.42 pyridyl]acetamide (2H, d, J = 8.5Hz), 5.54 (2H, br s), 3.89 (2H, s), 2.83-2.73 (4H, m), 2.50 (2H, m).

Η ₂ Ν 1 2-[4-(4-amino-7,8- MS Method 1 : Ή NMR (DMSO-d6, 400MHz) dihydro-6H- RT: 3.26 min, δ/ppm: 11.12 (1H, s), 8.75- cyclopenta[2,3]pyrrol m/z 483.4 8.72 (1H, m), 8.27 (1H, d,J =

HN N o[2,4-d]pyrimidin-5- [M+H] ⁺ 8.9Hz), 8.20-8.15 (1H, m), yl)-2-methoxy- 8.14 (1H, s), 7.41 (1H, d,J = phenyl]-N-[5- 8.0Hz), 7.08 (1H, d,J =

(trifluoromethyl)-2- 2.3Hz), 6.99 (1H, dd, J = pyridyl]acetamide 7.9Hz, 2.2Hz), 5.59 (2H, brs),

3.86 (2H, s), 3.81 (3H, s),

H ₂ N J 2.85-2.77 (4H, m), 2.50 (2H, m).

2-[4-(4-amino-7,8- MS Method 1 : Ή NMR (DMSO-d6, 400MHz) dihydro-6H- RT: 2.99 min, δ/ppm: 10.91 (1H, s), 8.62 (1H, cyclopenta[2,3]pyrrol m/z 483.4 d, J = 5.7Hz), 8.16 (2H, m), o[2,4-d]pyrimidin-5- [M+H] ⁺ 7.77 (1H, dd, J= 5.5Hz, yl)-2-methoxy- 2.0Hz), 7.42 (1H, d,J = phenyl]-N-[2- 7.9Hz), 7.10 (1H, d,J =

(trifluoromethyl)-4- 2.0Hz), 7.01 (1H, dd, J =

H ₂ N c J pyridyl]acetamide 7.9Hz, 2.0Hz), 5.63 (2H, brs),

3.81 (5H, s), 2.85-2.77 (4H, m), 2.50 (2H, m).

2-[4-(4-amino-7,8- MS Method 1 : Ή NMR (DMSO-d6, 400MHz) dihydro-6H- RT: 3.38 min, δ/ppm: 10.20 (1H, s), 8.43 (1H, cyclopenta[2,3]pyrrol m/z 500.4 d, J = 7.2Hz), 8.15 (1H, s), o[2,4-d]pyrimidin-5- [M+H] ⁺ 7.56-7.52 (2H, m), 7.41 (1H, d, yl)-2-methoxy- J = 8.0Hz), 7.09 (1H,d, J = phenyl]-N-[2-fluoro-5- 2.0Hz), 7.00 (1H, dd, J =

(trif I u o ro methyl) p h e n 7.8Hz, 2.1Hz), 5.59 (2H, brs), yl]acetamide 3.85 (2H, s), 3.83 (3H, s),

H ₂ N J 2.85-2.77 (4H, m), 2.50 (2H, m).

2-[4-(4-amino-7,8- MS Method 1 : Ή NMR (DMSO-d6, 400MHz)

IXX dihydro-6H- RT: 3.17 min, δ/ppm: 9.73 (1H, s), 8.16 (1H, cyclopenta[2,3]pyrrol m/z 446.4 s), 7.69 (1H,d, J = 6.9Hz), o[2,4-d]pyrimidin-5- [M+H] ⁺ 7.41 (1H, d, J= 8.0Hz), 7.16- yl)-2-methoxy- 7.07 (2H, m), 6.99 (1H, dd, J = phenyl]-N-(2-fluoro- 7.8Hz, 2.0Hz), 6.97-6.92 (1H,

5-methyl- m), 5.63 (2H, brs), 3.83 (3H, phenyl)acetamide s), 3.77 (2H, s), 2.85-2.77 (4H,

H ₂ N T m), 2.50 (2H, m), 2.23 (3H, s).

2-[4-(4-amino-7,8- MS Method 1 : Ή NMR (DMSO-d6, 400MHz) dihydro-6H- RT: 3.56 min, δ/ppm: 10.58 (1H, s), 8.25 (1H, cyclopenta[2,3]pyrrol m/z 517.0 d, J = 2.4Hz), 8.15(1 H, s), o[2,4-d]pyrimidin-5- [M+H] ⁺ 7.85 (1H, dd, J= 9.0Hz, yl)-2-methoxy- 2.5Hz), 7.67 (1H, d, J = phenyl]-N-[4-chloro- 8.9Hz), 7.41 (1H, d, J =

3- 8.1Hz), 7.09 (1H, d, J =

(trif I u o ro methyl) p h e n 2.0Hz), 7.00 (1H, dd, J =

H ₂ N J yl]acetamide 7.8Hz, 2.1Hz), 5.60 (2H, brs),

3.81 (3H, s), 3.76 (2H, s), 2.85-2.77 (4H, m), 2.50 (2H, m).

[00807] Example 7

[00808] General Method E

Scheme 74

[00809] 2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]py rimidin-5-yl)phenyl]-N- phenyl-acetamide

[00810] A solution of 2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]py rimidin-5- yl)phenyl]acetic acid (100mg, 0.32mmol), aniline (0.02ml_, 0.36mmol), (benzotriazol-1 - yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (157mg, 0.36mmol) and DIPEA (0.06ml_, 0.32mmol) in DMF (10ml_) was stirred at room temperature overnight. The DMF was removed in vacuo and the crude residue purified by preparative LCMS to give 2-[4-(4-amino-7,8- dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]pyrimidin-5-yl)pheny l]-N-phenyl-acetamide (41 mg, 0.1 1 mmol, 33% yield).

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 10.23 (1 H, s), 8.14 (1 H, s), 7.65-7.60 (2H, m), 7.55-7.50 (2H, m), 7.44-7.39 (2H, m), 7.35-7.28 (2H, m), 7.08-7.03 (1 H, m), 5.52 (2H, br s), 3.76 (2H, s), 2.83-2.73 (4H, m), 2.45 (2H, m, under DMSO).

MS Method 1 : RT: 2.85 min, m/z 384.2 [M+H] ⁺

[00811] The compounds shown in the table below were similarly prepared by varying the amine and acid shown in the reaction scheme for General Method E using acid Intermediate 8 and amine Intermediate 56 as well as commercially available amines:

[00812] Example 8 [00813] 2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]py rimidin-5-yl)-2- methoxy-phenyl]-N-phenyl-acetamide

[00814] Aniline (0.01 mL, 0.09mmol) was added to a solution of 2-[4-(4-amino-7,8-dihydro-6H- cyclopenta[2,3]pyrrolo[2,4-d]pyrimidin-5-yl)-2-methoxy-pheny l]acetic acid (30mg, 0.09mmol), 1 - hydroxybenzotriazole hydrate (20mg, 0.13mmol), and N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (25mg, 0.13mmol) in DMF (2mL). The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the resulting residue taken up in EtOAc. The organic layer was washed with brine (3x50ml_), dried over Na2S04 and solvent removed under reduced pressure. The resulting residue purified by preparative HPLC to yield 2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]py rimidin-5-yl)-2-methoxy- phenyl]-N-phenyl-acetamide (9mg, 0.02mmol, 24% yield).

Ή NMR (CD3OD, 400MHz) δ/ppm: 8.22 (1 H, s), 7.62-7.58 (2H, m), 7.45 (1 H, d, J = 7.9Hz), 7.36- 7.31 (2H, m), 7.14-7.07 (2H, m) 7.03 (1 H, dd, J = 7.8Hz, 2.0Hz), 3.90 (3H, s), 3.87 (2H, br s), 2.95 (2H, t, J = 6.9Hz), 2.87 (2H, t, J = 7.0Hz), 2.63-2.54 (2H, m).

MS Method 1 : RT: 2.93 min, m/z 414.4 [M+H] ⁺

[00815] Example 9

[00816] Synthesis of N-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]py rimidin-5- yl)phenyl]-2-(4-piperidyl)acetamide

Scheme 75

[00817] 2-[(6-bromo-3-pyridyl)amino]acetonitrile

[00818] To a solution of 5-amino-2-bromopyridine (10.00g, 57.80mmol) in THF (100ml_) was added bromoacetonitrile (8.05ml_, 1 15.6mmol) and Ν,Ν-diisopropylethylamine (20.14mL,

1 15.6mmol) and the resulting mixture was stirred at reflux overnight. LCMS showed conversion to product. The reaction mixture was allowed to cool to room temperature and EtOAc and sat. aq. NH4CI solution were added and the layers separated. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried over Na2S04, filtered and the solvent removed in vacuo to afford 2-[(6-bromo-3-pyridyl)amino]acetonitrile (12.28g, 57.80mmol, 100% yield).

MS Method 2: RT: 1 .22 min, m/z 212.0 [M+H] ⁺ , 214.0 [M+H] ⁺

[00819] 2-[(6-bromo-3-pyridyl)-(cyanomethyl)amino]cyclopentene-1 -carbonitrile

[00820] A solution of 2-[(6-bromo-3-pyridyl)amino]acetonitrile (17.00g, 80.17mmol) 2- oxocyclopentanecarbonitrile (10.50g, 96.2mmol) and p-toluenesulfonic acid monohydrate (1 .52g, 8.02mmol) in toluene (150ml_) was heated at 130 °C under Dean-Stark conditions for 30 hours. The reaction mixture was allowed to cool to room temperature and the solvent removed in vacuo. EtOAc (100ml_) and NaHC03 (100ml_) were added to the residue, the organic layer separated and the aqueous layer washed with EtOAc (2 x 50ml_) and the organics combined, washed with brine and dried with Na2S04. The solvents were removed in vacuo to give the crude product of 2-[(6-bromo-3- pyridyl)-(cyanomethyl)amino]cyclopentene-1 -carbonitrile (3.5g, 1 1 .54mmol, 14% yield).

MS Method 2: RT: 1 .51 min, m/z 302.9 [M+H] ⁺ , m/z 304.9 [M+H] ⁺

[00821] 3-amino-1 -(6-bromo-3-pyridyl)-5,6-dihydro-4H-cyclopenta[b]pyrrole-2 -carbonitrile [00822] A solution of 2-[(6-bromo-3-pyridyl)-(cyanomethyl)amino]cyclopentene-1 -carbonitrile (12.64g, 41 .69mmol) and sodium fe/ -butoxide (4.01 g, 41 .69mmol) in fe/ -butanol (100mL) was stirred at 80 °C for 1 .5 hours. LCMS indicated conversion to product. The reaction was allowed to cool to room temperature and EtOAc and sat. aq. NhUCI solution was added and the layers separated. The organic layer was washed with brine and then dried over anhydrous Na2S04, filtered and the solvent removed in vacuo to afford 3-amino-1 -(6-bromo-3-pyridyl)-5,6-dihydro-4H- cyclopenta[b]pyrrole-2-carbonitrile (12.64g, 41 .69mmol, 100% yield).

MS Method 2: RT: 1 .61 min, m/z 303.0 [M+H] ⁺ , 304.9 [M+H] ⁺

[00823] N-[5-(3-amino-2-cyano-5,6-dihydro-4H-cyclopenta[b]pyrrol-1 -yl)-2-pyridyl]-2 -phenyl- acetamide

[00824] 3-amino-1 -(6-bromo-3-pyridyl)-5,6-dihydro-4H-cyclopenta[b]pyrrole-2-c arbonitrile (400mg, 1 .32mmol) 2-phenylacetamide (357mg, 2.64mmol) 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (1 14mg, 0.20mmol) tris(dibenzylideneacetone)dipalladium (0) (60mg, 0.07mmol) and caesium carbonate (860mg, 2.64mmol) were weighed into a flask. This was evacuated and flushed with three times nitrogen and 1 ,4-dioxane (10ml_) was added. The mixture was heated to 80 °C overnight, with the reaction being followed by LCMS. The mixture was allowed to cool and water (50ml_) was added. This was extracted with EtOAc (3 x 50ml_) and the organics combined, dried over Na2S04 and the solvents removed in vacuo to give N-[5-(3-amino-2-cyano-5,6-dihydro- 4H-cyclopenta[b]pyrrol-1 -yl)-2-pyridyl]-2-phenyl-acetamide (100mg, 0.28mmol, 21 % yield) was taken onto the next step without further purification.

MS Method 2: RT: 1 .65 min, m/z 358.1 [M+H] ⁺

[00825] N-[5-(4-amino-7,8-dihydro-6H-cyclopenta[4,5]pyrrolo[1 ,2-d]pyrimidin-5-yl)-2-pyridyl]- 2-phenyl-acetamide

[00826] A solution of N-[5-(3-amino-2-cyano-5,6-dihydro-4H-cyclopenta[b]pyrrol-1 -yl)-2-pyridyl]-2- phenyl-acetamide (100mg, 0.28mmol) and formamidine acetate (1 16mg, 1 .12mmol) in EtOH (5ml_) was heated at 80 °C for 2 hours. LCMS showed conversion to product. The reaction mixture was allowed to cool to room temperature and the solvent removed in vacuo. EtOAc and water were added and the layers separated. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na2S04, filtered and the solvent removed in vacuo to afford ~1 OOmg of crude product. The crude residue was purified by reverse phase column chromatography using an eluent of 0-40% MeCN+0.1 % formic acid in H2O+0.1 % formic acid to give N-[5-(4-amino-7,8- dihydro-6H-cyclopenta[4,5]pyrrolo[1 ,2-d]pyrimidin-5-yl)-2-pyridyl]-2-phenyl-acetamide (20mg, 0.05mmol, 18% yield). Ή NMR (DMSO-d6, 400MHz) δ/ppm: 10.97 (1 H, s), 8.37 (1 H, dd, J = 2.8Hz, 0.8 Hz), 8.21 (1 H, d, J = 8.8Hz), 8.16 (1 H, s) 7.80 (1 H, dd, J = 2.8Hz, 8.8Hz) 7.35 (4H, m) 7.27 (1 H, tt, J = 1 .6Hz, 7.1 Hz) 5.81 (2H, s) 3.76 (2H, s) 2.78 (4H, m) 2.45 (2H).

MS Method 1 : RT: 2.81 min, m/z 385.3 [M+H] ⁺

[00827] Example 10

[00828] Synthesis of N-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]py rimidin-5- yl)phenyl]-2-(4-piperidyl)acetamide

[00829] A stirred solution of benzyl 4-[2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4- d]pyrimidin-5-yl)anilino]-2-oxo-ethyl]piperidine-1 -carboxylate (733mg, 1 .40mmol) in MeOH (40ml_) was placed under a N2 atmosphere. Palladium, 10 wt. % on carbon powder, dry (149mg) was added. The N2 was purged and the reaction was placed under H2. The reaction was left for 3 hours. The solution was filtered through celite, concentrated in vacuo then purified via reverse-phase column chromatography using an eluent of 20-80% MeCN in 1 % Formic Acid in H2O to yield N-[4- (4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]pyrimid in-5-yl)phenyl]-2-(4- piperidyl)acetamide (545mg, 1 .40mmol, 100% yield).

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 10.19 (1 H, s), 8.12 (1 H, s), 7.78 (2H, d, J = 8.4Hz), 7.36 (2H, d, J = 8.4Hz), 5.51 (2H, s), 3.33 (1 H, s), 2.93-2.86 (2H, m), 2.79 (2H, t, J = 7.3Hz), 2.72 (2H, t, J = 7.3Hz), 2.49-2.38 (4H, m), 2.24 (2H, d, J = 7.3Hz), 1 .90-1 .78 (1 H, m), 1 .63-1 .55 (2H, m), 1 .15-1 .03 (2H, m).

MS Method 1 : RT: 1 .88min, m/z 391 .2 [M+H] ⁺

[00830] Example 11

[00831] Synthesis of 2-(1 -acetyl-4-piperidyl)-N-[4-(4-amino-7,8-dihydro-6H- cyclopenta[2,3]pyrrolo[2,4-d]pyrimidin-5-yl)phenyl]acetamide

[00832] N-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]py rimidin-5-yl)phenyl]-2-(4- piperidyl)acetamide (50mg, 0.13mmol) and acetic anhydride (13.29μΙ_, 0.14mmol) were heated in DCM (3ml_) at 35 °C for 1 hour. The product was separated via SCX eluting with 2M Nhh in MeOH. The solvents were removed in vacuo to yield 2-(1 -acetyl-4-piperidyl)-N-[4-(4-amino-7,8-dihydro-6H- cyclopenta[2,3]pyrrolo[2,4-d]pyrimidin-5-yl)phenyl]acetamide (22mg, 0.05mmol, 40% yield) as an off-white solid.

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 10.16 (1 H, s), 8.13 (1 H, s), 7.77 (2H, d, J = 8.2Hz), 7.37 (2H, d, J = 8.2Hz), 5.54 (2H, s), 4.38-4.31 (1 H, m), 3.83-3.76 (1 H, m), 3.07-2.98 (1 H, m), 2.79 (2H, t, J = 7.7Hz), 2.73 (2H, t, J = 7.7Hz), 2.58-2.40 (3H, m), 2.30 (2H, d, J = 7.3Hz), 2.06-2.00 (1 H, m), 1 .99 (3H, s), 1 .76-1 .65 (2H, m), 1 .23-1 .1 1 (1 H, m), 1 .10-0.98 (1 H, m).

MS Method 1 : RT: 2.40min, m/z 433.2 [M+H] ⁺

[00833] Example 12

[00834] Synthesis of (2S)-2-amino-N-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyr rolo[2,4- d]pyrimidin-5-yl)phenyl]-2-phenyl-acetamide

Scheme 76

[00835] Benzyl N-[(1S)-2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[ 2,4-d]pyrimidin- 5-yl)anilino]-2-oxo-1 -phenyl-ethyl]carbamate

[00836] According to General Method A, the title compound was synthesised from Intermediate 2 and Intermediate 33, (250mg, 0.47mmol, 49% yield).

MS Method 2: RT: 1 .58min, m/z 533.4 [M+H] ⁺

[00837] (2S)-2-amino-N-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyr rolo[2,4-d]pyrimidin-5- yl)phenyl]-2-phenyl-acetamide

[00838] A stirred solution of benzyl N-[(1 S)-2-[4-(4-amino-7,8-dihydro-6H- cyclopenta[2,3]pyrrolo[2,4-d]pyrimidin-5-yl)anilino]-2-oxo-1 -phenyl-ethyl]carbamate (200mg, 0.38mmol) in MeOH (25ml_) was placed under a nitrogen atmosphere. Palladium, 10 wt. % on carbon powder, dry (40mg, 0.38mmol) was added. The nitrogen was purged and the reaction was placed under a hydrogen atmosphere. The reaction was left for 16 hours. The solution was filtered through celite and concentrated in vacuo. The residue was purified via reverse phase column chromatography using an eluent of 5-50% water + 0.1 % formic acid in acetonitrile + 0.1 % formic acid. The collected fractions were pooled and passed through SCX eluting with 2M NH3 in MeOH. Solvents were removed in vacuo to yield (2S)-2-amino-N-[4-(4-amino-7,8-dihydro-6H- cyclopenta[2,3]pyrrolo[2,4-d]pyrimidin-5-yl)phenyl]-2-phenyl -acetamide (16mg, 0.04mmol, 1 1 % yield) as a white solid.

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 8.12 (1 H, s), 7.82, (2H, d, J = 8.8Hz), 7.50 (2H, d, J = 8.8Hz), 7.39-7.24 (5H, m), 5.50 (2H, s), 4.58 (1 H, s), 2.78 (2H, t, J = 7.0Hz), 2.72 (2H, t, J = 7.0Hz), 2.48- 2.39 (2H, m).

MS Method 1 : RT: 2.12min, m/z 399.2 [M+H] ⁺

[00839] Example 13

[00840] In a similar manner to (2S)-2-amino-N-[4-(4-amino-7,8-dihydro-6H- cyclopenta[2,3]pyrrolo[2,4-d]pyrimidin-5-yl)phenyl]-2-phenyl -acetamide ( the compound of Example 12), (2S)-2-amino-N-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyr rolo[2,4-d]pyrimidin-5-yl)phenyl]- 3-phenyl-propanamide was made from Intermediate 2 and Intermediate 34.

[00841] benzyl N-[(1S)-2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[ 2,4-d]pyrimidin- 5-yl)anilino]-2-oxo-1 -phenyl-ethyl]carbamate

[00842] According to General Method A, the title compound was synthesised from Intermediate 2 and Intermediate 34, (175mg, 0.32mmol, 71 % yield).

MS Method 2: RT: 1 .58min, m/z 547.4 [M+H] ⁺

[00843] (2S)-2-amino-N-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyr rolo[2,4-d]pyrimidin-5- yl)phenyl]-3-phenyl-propanamide

[00844] benzyl N-[(1 S)-2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d ]pyrimidin-5- yl)anilino]-2-oxo-1 -phenyl-ethyl]carbamate was hydrogenated in a similar manner to benzyl N-[(1 S)- 2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]py rimidin-5-yl)anilino]-2-oxo-1 -phenyl- ethyl]carbamate (Example 12) to give (2S)-2-amino-N-[4-(4-amino-7,8-dihydro-6H- cyclopenta[2,3]pyrrolo[2,4-d]pyrimidin-5-yl)phenyl]-3-phenyl -propanamide (6mg, 0.02mmol, 5% yield).

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 8.13 (1 H, s), 7.78 (2H, d, J = 8.9Hz), 7.39 (2H, d, J = 8.9Hz), 7.37-7.18 (5H, m), 5.51 (2H, s), 3.70-3.65 (1 H, m), 3.05 (1 H, dd, J = 5.5Hz, J = 13.4Hz), 2.84-2.71 (5H, m), 2.47-2.40 (2H, m).

MS Method 1 : RT: 2.24min, m/z 413.2 [M+H] ⁺

[00845] Example 14

[00846] Synthesis of 4-[2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d ]pyrimidin- 5-yl)anilino]-2-oxo-ethyl]-2-(trifluoromethyl)benzamide

Scheme 77

[00847] N-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]py rimidin-5-yl)phenyl]-2- [4-cyano-3-(trifluoromethyl)phenyl]acetamide

[00848] According to General Method A, the title compound was synthesised from Intermediate 2 and Intermediate 36, (220mg, 0.46mmol, 61 % yield).

MS Method 2: RT: 1 .61 min, m/z 477.1 [M+H] ⁺

[00849] 4-[2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d ]pyrimidin-5-yl)anilino]- 2-oxo-ethyl]-2-(trifluoromethyl)benzamide

[00850] To a solution of N-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]py rimidin-5- yl)phenyl]-2-[4-cyano-3-(trifluoromethyl)phenyl]acetamide (1 10mg, 0.23mmol) in DMSO (3ml_) was added potassium carbonate (95mg, 0.69mmol), MgO (46mg, 1 .15mmol) and H2O2 solution 30 wt% in H2O (0.7mL, 24.64mmol). The resulting suspension was then stirred for 2 hours. The reaction mixture was then passed through an SCX cartridge and eluted with MeOHiNhh (5%). The crude product was then purified via reverse phase chromatography to give 4-[2-[4-(4-amino-7,8-dihydro- 6H-cyclopenta[2,3]pyrrolo[2,4-d]pyrimidin-5-yl)anilino]-2-ox o-ethyl]-2-(trifluoromethyl)benzamide (5mg, 0.01 mmol, 5% yield).

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 10.49 (1 H, s), 8.92 (1 H, s), 7.93 (1 H, s), 7.75 (3H, m), 7.66 (1 H, d, J = 7.6Hz), 7.58 (1 H, s), 7.53 (1 H, d, J = 7.6Hz), 7.38 (2H ,m), 5.51 (2H, s), 3.84 (2H, s), 2.79 (2H, m), 2.72 (2H, m), 2.46 (2H, m).

MS Method 1 : RT: 2.60 min, m/z 495.3 [M+H] ⁺

[00851] Example 15

[00852] Synthesis of N-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]py rimidin-5- yl)-2-methoxy-phenyl]-2-[4-(3-hydroxyoxetan-3-yl)phenyl]acet amide

[00853] To a solution of 2-[4-(3-hydroxyoxetan-3-yl)phenyl]acetic acid (Intermediate 40) (77mg, 0.37mmol) in dry DCM (2ml_) and DMF (200μΙ_) to help solubilizing all the starting material, was added 1 ,3-dicyclohexylcarbodiimide (38mg, 0.19mmol) and the mixture was stirred at room temperature for 1 hour. The cloudy mixture was filtered and the solid washed with DCM. The filtrate was concentrated in vacuo. The residue was dissolved in DMF (2ml_), 5-(4-amino-3-methoxy- phenyl)-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]pyrimidi n-4-amine (Intermediate 3) (50mg, 0.17mmol) was added and the mixture was stirred at room temperature for 24 hours. The mixture was then concentrated in vacuo. The residue was purified by preparative HPLC to give N-[4-(4- amino-7,8-dihydro-6/-/-cyclopenta[2,3]pyrrolo[2,4-d]pyrimidi n-5-yl)-2-methoxy-phenyl]-2-[4-(3- hydroxyoxetan-3-yl)phenyl]acetamide (21 mg, 0.04mmol, 26% yield) as a white solid.

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 9.47 (1 H, s), 8.17-8.12 (2H, m), 7.56 (2H, d, J = 8.0Hz), 7.38 (2H, d, J = 8.0Hz), 7.12 (1 H, d, J = 2.0Hz), 6.96 (1 H, dd, J = 8.5Hz, 2.0Hz), 6.39 (1 H, br s), 5.58 (2H, br s), 4.77 (2H, d, J = 6.4Hz), 4.68 (2H, d, J = 6.4Hz), 3.88 (3H, s), 3.80 (2H, s), 2.83-2.74 (4H, m), 2.50-2.40 (2H, m).

MS Method 1 : RT: 2.59 min, m/z 486.2 [M+H] ⁺

[00854] Example 16

[00855] N-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]py rimidin-5-yl)-2- (trifluoromethyl)phenyl]-2-[2-fluoro-5-(trifluoromethyl)phen yl]acetamide

[00856] 0-(Benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (171 mg, 0.45mmol) and N,N-diisopropylethylamine (0.1 1 ml_, 0.60mmol) were added to a solution of 5-[4- amino-3-(trifluoromethyl)phenyl]-7,8-dihydro-6/-/-cyclopenta [2,3]pyrrolo[2,4-d]pyrimidin-4-amine (Intermediate 76) (100mg, 0.30mmol) and 2-fluoro-5-(trifluoromethyl)phenylacetic acid (73mg, 0.33mmol) in THF (10ml_) and the resulting solution was heated to reflux for 4 hours. The solution was then cooled to room temperature and added to brine (40ml_). The product extracted with EtOAc (5 x 10mL). The organic layers were combined, washed with sat. aq. NaHC03 (50ml_), brine (50ml_), dried over Na2S04 and the concentrated in vacuo. The residue was purified by column chromatography using an eluent of 0-100% EtOAc in heptane followed by 0-20% MeOH in DCM to give a light brown film. Heptane was added which caused precipitation of a solid, which was filtered and dried to give N-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]py rimidin-5-yl)-2- (trifluoromethyl)phenyl]-2-[2-fluoro-5-(trifluoromethyl)phen yl]acetamide (60mg, 0.1 1 mmol, 37% yield) as a light pink solid.

Ή NMR (DMSO-d6, 400MHz) δ/ppm: 10.62 (1 H, s), 8.61 (1 H, s), 7.67 (1 H, m), 7.43-7.30 (2H, m), 7.27-7.22 (2H, m), 6.85 (1 H, d, J = 8.4Hz), 5.83 (2H, s, br), 3.34 (2H, s), 2.91 -2.78 (4H, m), 2.50- 2.43 (2H, m).

MS Method 1 : RT: 3.94 min, m/z 538.2 [M+H] ⁺

[00857] Example 17

[00858] CSF-1 R in vitro binding assay

[00859] Purified human CSF-1 R receptor (Invitrogen Life Tech. Cat No PR4598A) expressed in insect cells was used in these assays, the assays measured binding of small molecule inhibitors to the receptor tyrosine kinase. The detection method used was FRET (fluorescence resonance energy transfer) based platform technology Lanthascreen™ from Invitrogen.

[00860] The stock solutions of test compounds (10mM in DMSO) were diluted (1 :3.333) in DMSO in PlateOne (Starlabs, Cat No S1830-9600) followed by 10 fold log dilutions, in order to test eight concentrations of each compound. The compounds were further diluted 100 fold in the Kinase buffer (New England Bio-labs Cat No B6022S) to obtain 3X the desired concentration.

[00861] CSF-1 R enzyme, tracer 236 (Invitrogen Life Tech. Cat No PR9078A) and Eu-Anti-His

Antibody (Invitrogen Life Tech. Cat No PR9082A) were diluted in kinase buffer in order to obtain 3X the desired concentration. The assays were performed in triplicates and in 96 well half area white plates with 30μΙ as total reaction mixture (Costar, Cat No 3693). 10μΙ of the compounds diluted in kinase buffer were added first followed by 10μΙ of the diluted tracer. The reaction was initiated by adding 10μΙ of enzyme/antibody mixture.

[00862] The final concentrations of CSF-1 R enzyme, tracer 236 and Eu-anti-His antibody were 5nM, 37nM and 2nM respectively. The plates were sealed with Mylar plate sealers, centrifuged (l OOOrpm, 2 min) and incubated in the dark at room temperature for 1 to 5 hours

[00863] The FRET signal was measured on the PerkinElmer Envision, excitation 340nm

(Bandpass 10nm), emission 615nm (Bandpass 10nm) at one and five hours. The data generated was analysed using graph pad prism to obtain dose response curves and plC50 values for each compound. For each compound, independent experiments to generate N=2 data were performed and averaged to obtain the final plC50 value. [00864] Example 18

[00865] KDR (VEGF-2) in vitro binding assay

[00866] A number of tyrosine kinase inhibitors which show strong activity against cFMS, such as Axitinib and Linifanib, also show strong activity against KDR (VEGFR-2). Hypertension is emerging as one of the most common adverse effects of therapy with tyrosine kinase inhibitors which have high KDR activity and may lead to patients leaving treatment early or the agent falling out of clinical trials. Other side effects that have been observed with agents inhibiting KDR include fatigue, light- headedness/dizziness, ataxia, diarrhea, mucositis, skin toxicity and anorexia. One way of avoiding these side effects and provide an advantage over other agents would be to reduce the inhibitors affinity for KDR whilst maintaining activity at cFMS (Morabito, A., et. a/., The Oncologist, 2006, 753- 764).

[00867] Purified human KDR (VEGF-2) receptor (Invitrogen Life Tech. Cat No PR5992C) expressed in insect cells was used in these assays, the assays measured binding of small molecule inhibitors to the receptor tyrosine kinase. The detection method used was FRET (fluorescence resonance energy transfer) based platform technology Lanthascreen™ from Invitrogen.

[00868] The stock solutions of test compounds (10mM in DMSO) were diluted (1 :3.333) in DMSO in PlateOne (Starlabs, Cat No S1830-9600) followed by 10 fold log dilutions, in order to test eight concentrations of each compound. The compounds were further diluted 100 fold in the Kinase buffer (Lanthascreen™ Kinase Buffer 5X, Invitrogen Life Tech. Cat No PR4940D) to obtain 3X the desired concentrations.

[00869] KDR enzyme, tracer 236 (Invitrogen Life Tech. Cat No PR9078A) and Eu-Anti-His Antibody (Invitrogen Life Tech. Cat No PR9082A) were diluted in kinase buffer in order to obtain 3X the desired concentrations. The assays were performed in triplicates and in 96 well half area white plates with 30μΙ as total reaction mixture (Costar, Cat No 3693). 10μΙ of the compounds diluted in kinase buffer were added first followed by 10μΙ of the diluted tracer. The reaction was initiated by adding 10μΙ of enzyme/antibody mixture.

[00870] The final concentrations of KDR enzyme, tracer 236 and Eu-anti-His antibody were 2.5nM, 25nM and 2nM respectively. The plates were sealed with Mylar plate sealers, centrifuged (l OOOrpm, 2 min) and incubated in the dark at room temperature for 1 to 5 hours

[00871] The FRET signal was measured on the PerkinElmer Envision, excitation 340nm

(Bandpass 10nm), emission 615nm (Bandpass 10nm) at one and five hours. The data generated was analysed using graph pad prism to obtain dose response curves and plC50 values for each compound. For each compound, independent experiments to generate N=2 data were performed and averaged to obtain the final plC50 value.

[00872] The results of the in vitro biological data for certain compounds of the invention are given in Table 12 below. The table shows the cFMS and KDR inhibition activity of each compound characterised based on the IC50 value of the compound as "+", "++" and "+++". The category "+" refers to compounds with an IC50 of greater than 200 nM. The category "++" refers to compounds with an IC50 of 10 nM to 200 nM. The category "+++" refers to compounds with an IC50 of <10 nM. The category "-" refers to compounds that had an IC50 value that was above the upper limit of the present assays. No entry indicates that the compound has not been tested. cFMS KDR

ID

Compound IC50 IC50 No.

(5Hr) (5Hr)

/V-[4-(4-amino-7,8-dihydro-6/-/-cyclopenta[2,3]pyrrolo[2, 4-c ]pyrimidin-5-

1 +++ +

yl)phenyl]-2-[2-fluoro-5-(trifluoromethyl)phenyl]acetamide

/V-[4-(4-amino-7,8-dihydro-6/-/-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

2 ++ +

yl)phenyl]-2-phenyl-acetamide

/V-[4-(4-amino-7,8-dihydro-6/-/-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

3 +++ - yl)phenyl]-2-(2-methoxyphenyl)acetamide

/V-[4-(4-amino-7,8-dihydro-6/-/-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

4 +++ +

yl)phenyl]-2-(3-methoxyphenyl)acetamide

/V-[4-(4-amino-7,8-dihydro-6/-/-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

5 +++ +

yl)phenyl]-2-(4-methoxyphenyl)acetamide

/V-[4-(4-amino-7,8-dihydro-6/-/-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

6 ++ - yl)phenyl]-3-phenyl-propanamide

/V-[4-(4-amino-7,8-dihydro-6/-/-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

7 + +

yl)phenyl]-2-(3,5-dimethoxyphenyl)acetamide

/V-[4-(4-amino-7,8-dihydro-6/-/-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

8 + - yl)phenyl]-2-(4-pyridyl)acetamide

/V-[4-(4-amino-7,8-dihydro-6/-/-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

9 ++ - yl)phenyl]-2-(3-pyridyl)acetamide

/V-[4-(4-amino-7,8-dihydro-6/-/-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

10 + - yl)phenyl]-2-fluoro-2-phenyl-acetamide

/V-[4-(4-amino-7,8-dihydro-6/-/-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

1 1 + - yl)phenyl]-2-(4-methylpiperazin-1 -yl)acetamide

/V-[4-(4-amino-7,8-dihydro-6/-/-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

12 + - yl)phenyl]-2-imidazol-1 -yl-acetamide

/V-[4-(4-amino-7,8-dihydro-6/-/-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

13 + - yl)phenyl]-2-morpholino-acetamide

/V-[4-(4-amino-7,8-dihydro-6/-/-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

14 + - yl)phenyl]-2-pyrrolidin-1 -yl-acetamide

/V-[4-(4-amino-7,8-dihydro-6/-/-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

15 +++ +

yl)phenyl]-2-(3,4-dichlorophenyl)acetamide

/V-[4-(4-amino-7,8-dihydro-6/-/-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

16 - +

yl)phenyl]-2-[4-(trifluoromethoxy)phenyl]acetamide

/V-[4-(4-amino-7,8-dihydro-6/-/-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

17 +++ +

yl)phenyl]-2-(4-fluorophenyl)acetamide

/V-[4-(4-amino-7,8-dihydro-6/-/-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

18 +++ +

yl)phenyl]-2-(3-chlorophenyl)acetamide

/V-[4-(4-amino-7,8-dihydro-6/-/-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

19 +++ +

yl)phenyl]-2-[3-(trifluoromethoxy)phenyl]acetamide A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-(^p yrimidin-5-

+++ + yl)phenyl]-2-(3-fluoro-4-methoxy-phenyl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

++ + yl)phenyl]-2-(4-fluoro-3-methoxy-phenyl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

+++ + yl)phenyl]-2-(2-bromo-4-fluoro-phenyl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

+++ + yl)phenyl]-2-(2-fluoro-4-methoxy-phenyl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

++ - yl)phenyl]-2-(4-hydroxyphenyl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

- + yl)phenyl]-2-(3-hydroxyphenyl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

+++ yl)phenyl]-2-(4-cyanophenyl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

++ - yl)phenyl]-2-[2-chloro-5-(trifluoromethyl)phenyl]acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

++ - yl)phenyl]-2-[4-chloro-3-(trifluoromethyl)phenyl]acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

++ + yl)phenyl]-2-[3-(difluoromethoxy)phenyl]acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

++ - yl)phenyl]-2-(1 ,3-benzodioxol-5-yl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

++ - yl)-2-methoxy-phenyl]-2-[2-fluoro-5-(trifluoromethyl)phenyl] acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

+++ + yl)phenyl]-2-(6-methoxy-3-pyridyl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

++ - yl)-2-methoxy^henyl]-2-[4-chloro-3-(trifluoromethyl)phenyl]a cetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

+++ - yl)-2-methoxy-phenyl]-2-(2-pyridyl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

+++ + yl)phenyl]-2-[2-(trifluoromethyl)-4-pyridyl]acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

++ - yl)-2-methoxy-phenyl]-2-phenyl-acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

++ + yl)phenyl]-2-[4-(trifluoromethyl)-2-pyridyl]acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

++ - yl)-2-methoxy-phenyl]-2-(6-methoxy-2-pyridyl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

++ - yl)phenyl]-2-(6-methoxy-2-pyridyl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

+++ ++ yl)phenyl]-2-(2,6-difluoro-4-methoxy-phenyl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

+++ + yl)phenyl]-2-(5-chloro-2-fluoro-phenyl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

+++ + yl)phenyl]-2-(4-chloro-2-fluoro-phenyl)acetamide A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-(^p yrimidin-5-

+++ + yl)phenyl]-2-(3-chloro-2-fluoro-phenyl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

+++ - yl)-2-methoxy-phenyl]-2-[6-(trifluoromethyl)-3-pyridyl]aceta mide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

+++ + yl)phenyl]-2-[6-(trifluoromethyl)-3-pyridyl]acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

+++ + yl)phenyl]-2-(4-chlorophenyl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

+++ + yl)-2-methoxy-phenyl]-2-(2-fluoro-4-methoxy-phenyl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

+++ + yl)phenyl]-2-[4-fluoro-2-(trifluoromethyl)phenyl]acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

+++ +++ yl)phenyl]-2-(3-bromo-4-methoxy-phenyl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

++ - yl)phenyl]-2-(4-chloro-2,6-difluoro-phenyl)acetamide

/V-[4-(4-amino-7,8-dihydro-6/-/-cyclopenta[4,5]pyrrolo[1 ,2-c ]pyrimidin-5-

++ + yl)phenyl]-2-(5-methoxy-2-pyridyl)acetamide

/V-[4-(4-amino-7,8-dihydro-6/-/-cyclopenta[4,5]pyrrolo[1 ,2-c ]pyrimidin-5-

++ - yl)-2-methoxy-phenyl]-2-(5-methoxy-2-pyridyl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

+++ + yl)-2-methoxy-phenyl]-2-(2-fluoro-5-methyl-phenyl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

+++ + yl)phenyl]-2-(2-fluoro-5-methyl-phenyl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

++ yl)phenyl]-2-(3-fluoro-5-methyl-2-pyridyl)acetamide

A/-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-c ]pyrimidin-5-yl)phenyl]-2-

+++ - phenyl-acetamide

A/-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-c ]pyrimidin-5-yl)-2-

+++ - methoxy-phenyl]-2-phenyl-acetamide

A/-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-c ]pyrimidin-5-yl)phenyl]-2-

++

(2-fluoro-4-methoxy-phenyl)acetamide

2-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-c ]pyrimidin-5-yl)phenyl]-/V-

++ +

[2-fluoro-5-(trifluoromethyl)phenyl]acetamide

A/-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-c ]pyrimidin-5-yl)phenyl]-2-

++ + (2-fluoro-5-methyl-phenyl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

+++ + yl)phenyl]-2-(2,4-dimethoxyphenyl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

++ + yl)-2-fluoro-phenyl]-2-[2-fluoro-5-(trifluoromethyl)phenyl]a cetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

+ + yl)phenyl]-1 H-indole-3-carboxamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

++ - yl)phenyl]-4-morpholino-butanamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

++ - yl)phenyl]-1 -methyl-indole-3-carboxamide A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-(^p yrimidin-5-

+ yl)phenyl]-2-(1 -methylpyrazol-3-yl)acetamide

A/-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-c ]pyrimidin-5-yl)-2-

++ - methoxy-phenyl]-2-[2-fluoro-5-(trifluoromethyl)phenyl]acetam ide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

++ - yl)-2-methoxy-phenyl]-2-(3-fluoro-5-methyl-2-pyridyl)acetami de

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

+ yl)-2-fluoro-phenyl]-2-phenyl-acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

++ + yl)-2-fluoro-phenyl]-2-(2-fluoro-4-methoxy-phenyl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

++ + yl)-3-fluoro-phenyl]-2-phenyl-acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

++ yl)phenyl]-2-(1 -methylpyrazol-4-yl)acetamide

benzyl 4-[2-[4-(4-amino-7,8-dihydro-6/-/-cyclopenta[2,3]pyrrolo[2,4 -

++ - c ]pyrimidin-5-yl)anilino]-2-oxo-ethyl]piperidine-1 -carboxylate

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

+ + yl)phenyl]-2-(4-piperidyl)acetamide

2-(1 -acetyl-4-piperidyl)-/V-[4-(4-amino-7,8-dihydro-6/-/-

+ - cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-yl)phenyl]acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

+++ + yl)phenyl]-2-(1 -methylindol-5-yl)acetamide

A/-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-c ]pyrimidin-5-yl)-2-

++ - methoxy-phenyl]-2-(2-fluoro-5-methyl-phenyl)acetamide

A/-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-(i]pyrimidin- 5-yl)phenyl]-2-

++ + (1 -methylindol-5-yl)acetamide

A/-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-c ]pyrimidin-5-yl)-2-fluoro-

+ - phenyl]-2-(2-fluoro-4-methoxy-phenyl)acetamide

A/-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-c ]pyrimidin-5-yl)-2-fluoro-

+ + phenyl]-2-phenyl-acetamide

A/-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-c ]pyrimidin-5-yl)-2-fluoro-

++ + phenyl]-2-[2-fluoro-5-(trifluoromethyl)phenyl]acetamide

A/-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-c ]pyrimidin-5-yl)-2-fluoro-

+ - phenyl]-2-(2-fluoro-5-methyl-phenyl)acetamide

A/-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-c ]pyrimidin-5-yl)-2-

+++ + methoxy-phenyl]-2-[4-(trifluoromethoxy)phenyl]acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

+ + yl)phenyl]-3-(1 H-indol-3-yl)propanamide

A/-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-c ]pyrimidin-5-yl)-2-

++ - methoxy-phenyl]-2-(3-fluoro-4-methoxy-phenyl)acetamide

A/-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-c ]pyrimidin-5-yl)-2-

+++ - methoxy-phenyl]-2-[4-chloro-3-(trifluoromethyl)phenyl]acetam ide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

+++ + yl)-2-methoxy-phenyl]-2-[4-(trifluoromethoxy)phenyl]acetamid e

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

+++ - yl)-2-methoxy-phenyl]-2-(3-fluoro-4-methoxy-phenyl)acetamide A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-(^p yrimidin-5-

89 +++ - yl)-2-methoxy-phenyl]-2-(3-fluoro-4-methyl-phenyl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

90 +++ - yl)-2-methoxy-phenyl]-2-(4-methoxy-3-methyl-phenyl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

91 +++ - yl)-2-methoxy-phenyl]-2-(2-fluoro-4-methyl-phenyl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

92 +++ ++

yl)phenyl]-2-(2-fluoro-4-methyl-phenyl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

93 ++ - yl)phenyl]-3-(1 -methylindol-3-yl)propanamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

94 +++ - yl)-2-methoxy-phenyl]-2-(1 -methylindol-5-yl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

95 +++ +

yl)phenyl]-2-(3-fluoro-4-methyl-phenyl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

96 +++ +

yl)phenyl]-2-(4-methoxy-3-methyl-phenyl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

97 +++ +

yl)phenyl]-2-[1 -(2,2,2-trifluoroethyl)indolin-5-yl]acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

98 +++ + yl)-2-methoxy-phenyl]-2-[1 -(2,2,2-trifluoroethyl)indolin-5-yl]acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

99 +++ - yl)phenyl]-2-(1 -methylpyrrolo[2,3-b]pyridin-5-yl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

100 +++ - yl)-2-methoxy-phenyl]-2-(1 -methylpyrrolo[2,3-b]pyridin-5-yl)acetamide

A/-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-c ]pyrimidin-5-yl)-2-

101 ++ - methoxy-phenyl]-2-(1 -methylpyrrolo[2,3-b]pyridin-5-yl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

102 +++ - yl)-2-methoxy-phenyl]-2-[2-(trifluoromethyl)-4-pyridyl]aceta mide

A/-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-c ]pyrimidin-5-yl)-2-

103 ++ - methoxy-phenyl]-2-[2-(trifluoromethyl)-4-pyridyl]acetamide

A/-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-c ]pyrimidin-5-yl)phenyl]-2-

104 +++ +

[4-chloro-3-(trifluoromethyl)phenyl]acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

105 +++ +

yl)phenyl]-2-indan-5-yl-acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

106 ++ - yl)phenyl]-2-(1 -phenylpyrazol-4-yl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

107 +++ +

yl)phenyl]-2-(3-methoxy-4-methyl-phenyl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

108 +++ - yl)-2-methoxy-phenyl]-2-(3-methoxy-4-methyl-phenyl)acetamide

A/-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-c ]pyrimidin-5-yl)phenyl]-2-

109 ++ +

(3-methoxy-4-methyl-phenyl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

1 10 ++ +

yl)phenyl]-2-(3-isopropyl-1 -methyl-indol-5-yl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

1 1 1 ++ - yl)-2-methoxy-phenyl]-2-(6-methoxy-3-pyridyl)acetamide /V-[4-(4-amino-6,8-dihydro-5/-/-furo[5,6]cyclopenta[1 ,2-c/]pyrimidin-5-yl)-

++ - 2-methoxy-phenyl]-2-(6-methoxy-3-pyridyl)acetamide

A/-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-c ]pyrimidin-5-yl)phenyl]-2-

++ - [6-(trifluoromethyl)-3-pyridyl]acetamide

A/-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-c ]pyrimidin-5-yl)phenyl]-2-

+++ +

[4-(trifluoromethoxy)phenyl]acetamide

A/-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-c ]pyrimidin-5-yl)phenyl]-2-

++ - (3-fluoro-4-methoxy-phenyl)acetamide

A/-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-c ]pyrimidin-5-yl)phenyl]-2-

++ - (3-fluoro-4-methyl-phenyl)acetamide

A/-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-c ]pyrimidin-5-yl)phenyl]-2-

+++ + (4-methoxy-3-methyl-phenyl)acetamide

A/-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-c ]pyrimidin-5-yl)phenyl]-2-

++ + (2-fluoro-4-methyl-phenyl)acetamide

A/-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-c ]pyrimidin-5-yl)-2-

++ - methoxy-phenyl]-2-[6-(trifluoromethyl)-3-pyridyl]acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

++ + yl)phenyl]-2-phenyl-propanamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

++ - yl)phenyl]-2-(2-phenyloxazol-4-yl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

+++ - yl)-2-methoxy^henyl]-2-[6-(trifluoromethyl)pyridazin-3-yl]ac etamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

++ - yl)-2-methoxy-phenyl]-2-(2-phenyloxazol-4-yl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

++ + yl)phenyl]-2-(1 ,3-benzothiazol-2-yl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

++ + yl)phenyl]-2-(6-chloropyridazin-3-yl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

++ - yl)phenyl]-2-[3-(dimethylamino)-4-(trifluoromethyl)phenyl]ac etamide

A/-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-c ]pyrimidin-5-yl)phenyl]-2-

+ - (6-chloropyridazin-3-yl)acetamide

A/-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-c ]pyrimidin-5-yl)phenyl]-2-

++ - [6-(trifluoromethyl)pyridazin-3-yl]acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

+ - yl)-2-methoxy-phenyl]-2-pyrazin-2-yl-acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

++ + yl)phenyl]-2-(3-methylisoxazol-5-yl)acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

++ + yl)phenyl]-2-[3-(dimethylamino)-4-methoxy-phenyl]acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

+++ + yl)phenyl]-2-[4-methoxy-3-(trifluoromethyl)phenyl]acetamide

A/-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-c ]pyrimidin-5-yl)phenyl]-2-

+++ +

[4-methoxy-3-(trifluoromethyl)phenyl]acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

++ + yl)-2-methoxy-phenyl]-2-[4-methoxy-3-(trifluoromethyl)phenyl ]acetamide A/-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-c ]pyrimidin-5-yl)-2-

135 +++ - methoxy-phenyl]-2-[4-methoxy-3-(trifluoromethyl)phenyl]aceta mide

(2S)-2-amino-/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]py rrolo[2,4-

136 + - c ]pyrimidin-5-yl)phenyl]-2-phenyl-acetamide

(2S)-2-amino-/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]py rrolo[2,4-

137 + - c ]pyrimidin-5-yl)phenyl]-3-phenyl-propanamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

138 ++ +

yl)phenyl]-2-[6-(trifluoromethyl)pyridazin-3-yl]acetamide

A/-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-c ]pyrimidin-5-yl)-2-

139 ++ - methoxy-phenyl]-2-[6-(trifluoromethyl)pyridazin-3-yl]acetami de

A/-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-c ]pyrimidin-5-yl)phenyl]-2-

140 ++ - [2-(trifluoromethyl)-4-pyridyl]acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

141 ++ - yl)-2-methoxy-phenyl]-2-(3-methylisoxazol-5-yl)acetamide

A/-[5-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

142 + - yl)-2-pyridyl]-2-phenyl-acetamide

4-[2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-

143 ++ - 5-yl)anilino]-2-oxo-ethyl]-2-(trifluoromethyl)benzamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

144 ++ +

yl)phenyl]-/V-phenyl-acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

145 +++ ++

yl)phenyl]-/V-[2-fluoro-5-(trifluoromethyl)phenyl]acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

146 + - yl)phenyl]-/V-(3-pyridyl)acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

147 ++ - yl)-2-methoxy-phenyl]-/V-phenyl-acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

148 +++ +

yl)phenyl]-/V-(1 -methylindol-5-yl)acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

149 +++ ++

yl)phenyl]-/V-(2-fluoro-5-methyl-phenyl)acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

150 +++ +

yl)phenyl]-/V-[4-chloro-3-(trifluoromethyl)phenyl]acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

151 ++ - yl)phenyl]-/V-benzyl-acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

152 ++ +

yl)phenyl]-/V-(2-fluoro-4-methoxy-phenyl)acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

153 ++ +

yl)phenyl]-/V-(6-methoxy-3-pyridyl)acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

154 ++ +

yl)phenyl]-/V-[5-(trifluoromethyl)-2-pyridyl]acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

155 ++ +

yl)phenyl]-/V-[6-(trifluoromethyl)-3-pyridyl]acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

156 + - yl)phenyl]-/V-(6-methoxypyridazin-3-yl)acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

157 +++ ++

yl)phenyl]-/V-[4-methoxy-3-(trifluoromethyl)phenyl]acetamide 2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-(^py rimidin-5-

158 ++ ++

yl)phenyl]-/V-[2-(trifluoromethyl)-4-pyridyl]acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

159 ++ +

yl)phenyl]-/V-[4-(trifluoromethoxy)phenyl]acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

160 +++ +

yl)phenyl]-/V-[3-chloro-4-(trifluoromethyl)phenyl]acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

161 +++ +

yl)phenyl]-/V-(3,4-dichlorophenyl)acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

162 +++ ++

yl)phenyl]-/V-indan-5-yl-acetamide

2-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-c ]pyrimidin-5-yl)phenyl]-/V-

163 +++ +

[4-chloro-3-(trifluoromethyl)phenyl]acetamide

2-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-c ]pyrimidin-5-yl)phenyl]-/V-

164 ++ +

(2-fluoro-5-methyl-phenyl)acetamide

2-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-c ]pyrimidin-5-yl)phenyl]-/V-

165 ++ +

[4-(trifluoromethoxy)phenyl]acetamide

2-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-c ]pyrimidin-5-yl)phenyl]-/V-

166 +++ ++

[4-methoxy-3-(trifluoromethyl)phenyl]acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

167 ++ - yl)phenyl]-/V-cyclohexyl-acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

168 + +

yl)phenyl]-/V-tetrahydropyran-4-yl-acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

169 ++ - yl)phenyl]-/V-[2-(trifluoromethyl)pyrimidin-5-yl]acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

170 ++ +

yl)phenyl]-/V-[6-(trifluoromethyl)pyridazin-3-yl]acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

171 +++ +

yl)phenyl]-/V-(3-fluoro-4-methoxy-phenyl)acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

172 +++ +

yl)phenyl]-1 -(2,3-dihydro-1 ,4-benzoxazin-4-yl)ethanone

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

173 +++ +++

yl)phenyl]-/V-(5-tert-butyl-2-phenyl-pyrazol-3-yl)acetamide

2-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-c ]pyrimidin-5-yl)phenyl]-/V-

174 ++ +

[5-(trifluoromethyl)-2-pyridyl]acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

175 ++ +

yl)phenyl]-/V-[4-(trifluoromethyl)thiazol-2-yl]acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

176 +++ +

yl)-2-methoxy-phenyl]-/V-[4-(trifluoromethoxy)phenyl]acetami de

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

177 +++ +

yl)-2-methoxy-phenyl]-/V-(3-fluoro-4-methoxy-phenyl)acetamid e

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

178 +++ - yl)-2-methoxy-phenyl]-1 -(2,3-dihydro-1 ,4-benzoxazin-4-yl)ethanone

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

179 +++ - yl)-2-methoxy-phenyl]-/V-(2-fluoro-4-methoxy-phenyl)acetamid e 2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-(^py rimidin-5-

180 yl)-2-methoxy-phenyl]-/V-[4-methoxy-3- +++ +

(trifluoromethyl)phenyl]acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

181 +++ +

yl)-2-methoxy-phenyl]-/V-(3,4-dichlorophenyl)acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

182 +++ - yl)-2-methoxy-phenyl]-/V-[5-(trifluoromethyl)-2-pyridyl]acet amide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

183 +++ +

yl)-2-methoxy-phenyl]-/V-[2-(trifluoromethyl)-4-pyridyl]acet amide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

184 +++ + yl)-2-methoxy^henyl]-/V-[2-fluoro-5-(trifluoromethyl)phenyl] acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

185 +++ - yl)-2-methoxy-phenyl]-/V-(2-fluoro-5-methyl-phenyl)acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

186 +++ + yl)-2-methoxy^henyl]-/V-[4-chloro-3-(trifluoromethyl)phenyl] acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

187 ++ +

yl)phenyl]-/V-[4-(trifluoromethyl)oxazol-2-yl]acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-c ]pyrimidin-5-

188 +++ - yl)-2-methoxy-phenyl]-/V-[6-(trifluoromethyl)-3-pyridyl]acet amide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[4,5]pyrrolo[1 ,2-d]pyrimidin-5-

189 ++

yl)-2-methoxy-phenyl]-2-(3-oxo-1 ,4-benzoxazin-4-yl)acetamide

/V-[4-(4-amino-6,8-dihydrofuro[4,5]pyrrolo[1 ,2-d]pyrimidin-5-yl)-2-

190 +

methoxy-phenyl]-2-(3-oxo-1 ,4-benzoxazin-4-yl)acetamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[4,5]pyrrolo[1 ,2-d]pyrimidin-5-

191 ++

yl)-2-methoxy^henyl]-2-[4-(trifluoromethyl)pyrimidin-2-yl]ac etamide

/V-[4-(4-amino-6,8-dihydrofuro[4,5]pyrrolo[1 ,2-d]pyrimidin-5-yl)-2-

192 +

methoxy-phenyl]-2-[4-(trifluoromethyl)pyrimidin-2-yl]acetami de

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[4,5]pyrrolo[1 ,2-d]pyrimidin-5-

193 ++

yl)-2-methoxy^henyl]-2-[2-(trifluoromethyl)pyrimidin-4-yl]ac etamide

/V-[4-(4-amino-6,8-dihydrofuro[4,5]pyrrolo[1 ,2-d]pyrimidin-5-yl)-2-

194 +

methoxy-phenyl]-2-[2-(trifluoromethyl)pyrimidin-4-yl]acetami de

/V-[4-(4-amino-6,8-dihydrofuro[4,5]pyrrolo[1 ,2-d]pyrimidin-5-yl)-2-

195 +

methoxy-phenyl]-2-(2,3-dihydro-1 ,4-benzoxazin-4-yl)acetamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]p yrimidin-5-

196 +

yl)-2-chloro-phenyl]-2-phenyl-acetamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[4,5]pyrrolo[1 ,2-d]pyrimidin-5-

197 ++

yl)-2-methoxy-phenyl]-2-(2,3-dihydro-1 ,4-benzoxazin-4-yl)acetamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[4,5]pyrrolo[1 ,2-d]pyrimidin-5-

198 yl)-2-methoxy-phenyl]-2-(6-fluoro-3,4-dihydro-2H-quinolin-1 - ++

yl)acetamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]p yrimidin-5-

199 +

yl)-2-(trifluoromethoxy)phenyl]-2-phenyl-acetamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]p yrimidin-5-

200 +

yl)-2-methoxy^henyl]-2-[4-(trifluoromethyl)pyridazin-3-yl]ac etamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]p yrimidin-5-

201 +

yl)-2-methoxy-phenyl]-2-(1 -methylpyrazol-3-yl)acetamide A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]p yrimidin-5-

202 ++

yl)-2-methoxy-phenyl]-2-(1 -methylpyrazol-4-yl)acetamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4- d]pyrimidin-5-

203 + yl)-2-methoxy-phenyl]-2-(2-methyl-1 -oxo-isoindolin-5-yl)acetamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]p yrimidin-5-

204 yl)-2-methoxy-phenyl]-2-[2-methyl-5-(trifluoromethyl)pyrazol -3- ++

yl]acetamide

4-[2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[4,5]pyrrolo[1 ,2-d]pyrimidin-

205 +

5-yl)-2-methoxy-anilino]-2-oxo-ethyl]-N-methyl-benzamide

4-[2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[4,5]pyrrolo[1 ,2-d]pyrimidin-

206 ++

5-yl)-2-methoxy-anilino]-2-oxo-ethyl]-N,N-dimethyl-benzamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[4,5]pyrrolo[1 ,2-d]pyrimidin-5-

207 +++

yl)-2-methoxy-phenyl]-2-(3,5-dimethoxyphenyl)acetamide

/V-[4-(4-amino-6,8-dihydrofuro[4,5]pyrrolo[1 ,2-d]pyrimidin-5-yl)-2-

208 ++

methoxy-phenyl]-2-(3,5-dimethoxyphenyl)acetamide

/V-[4-(4-amino-6,8-dihydrofuro[4,5]pyrrolo[1 ,2-d]pyrimidin-5-yl)-2-

209 ++

methoxy-phenyl]-2-(2-fluoro-4-methoxy-phenyl)acetamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[4,5]pyrrolo[1 ,2-d]pyrimidin-5-

210 +

yl)-2-methoxy-phenyl]-2-(3,5-dimethylisoxazol-4-yl)acetamide

/V-[4-(4-amino-6,8-dihydrofuro[4,5]pyrrolo[1 ,2-d]pyrimidin-5-yl)-2-

21 1 +++

methoxy-phenyl]-2-(3-methoxy-2-methyl-phenyl)acetamide

/V-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-d]pyrimidi n-5-yl)-2-

212 +++

methoxy-phenyl]-2-(2-fluoro-4-methyl-phenyl)acetamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[4,5]pyrrolo[1 ,2-d]pyrimidin-5-

213 +++ yl)-2-methoxy-phenyl]-2-[3-(trifluoromethyl)pyrazol-1 -yl]acetamide

/V-[4-(4-amino-6,8-dihydrofuro[4,5]pyrrolo[1 ,2-d]pyrimidin-5-yl)-2-

214 ++

methoxy-phenyl]-2-[3-(trifluoromethyl)pyrazol-1 -yl]acetamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[4,5]pyrrolo[1 ,2-d]pyrimidin-5-

215 +++ yl)-2-methoxy-phenyl]-2-[4-(trifluoromethyl)pyrazol-1 -yl]acetamide

/V-[4-(4-amino-6,8-dihydrofuro[4,5]pyrrolo[1 ,2-d]pyrimidin-5-yl)-2-

216 ++

methoxy-phenyl]-2-[4-(trifluoromethyl)pyrazol-1 -yl]acetamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[4,5]pyrrolo[1 ,2-d]pyrimidin-5-

217 yl)-2-methoxy-phenyl]-2-[3-methyl-5-(trifluoromethyl)pyrazol -1 - ++

yl]acetamide

/V-[4-(4-amino-6,8-dihydrofuro[4,5]pyrrolo[1 ,2-d]pyrimidin-5-yl)-2-

218 + methoxy^henyl]-2-[3-methyl-5-(trifluoromethyl)pyrazol-1 -yl]acetamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[4,5]pyrrolo[1 ,2-d]pyrimidin-5-

219 ++

yl)-2-methoxy-phenyl]-2-(3,5-dimethylpyrazol-1 -yl)acetamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4- d]pyrimidin-5-

220 +++ yl)-2-methoxy-phenyl]-2-[1 -(difluoromethyl)pyrazol-4-yl]acetamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]p yrimidin-5-

221 +++ yl)-2-methoxy-phenyl]-2-[5-(trifluoromethyl)isoxazol-3-yl]ac etamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]p yrimidin-5-

222 +

yl)-2-(trifluoromethyl)phenyl]-2-phenyl-acetamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[4,5]pyrrolo[1 ,2-d]pyrimidin-5-

223 +++

yl)-2-methoxy-phenyl]-2-(4-methylpyrazol-1 -yl)acetamide /V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[4,5]pyrrolo[1 ,2-d]pyrimidin-5-

224 ++ yl)-2-methoxy^henyl]-2-[4-(trifluoromethyl)imidazol-1 -yl]acetamide

/V-[4-(4-amino-6,8-dihydrofuro[4,5]pyrrolo[1 ,2-d]pyrimidin-5-yl)-2-

225 ++

methoxy-phenyl]-2-[4-(trifluoromethyl)imidazol-1 -yl]acetamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[4,5]pyrrolo[1 ,2-d]pyrimidin-5-

226 +++

yl)phenyl]-2-[3-(trifluoromethyl)pyrazol-1 -yl]acetamide

/V-[4-(4-amino-6,8-dihydrofuro[4,5]pyrrolo[1 ,2-d]pyrimidin-5-yl)phenyl]-2-

227 ++

[4-(trifluoromethyl)pyrazol-1 -yl]acetamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[4,5]pyrrolo[1 ,2-d]pyrimidin-5-

228 +++

yl)phenyl]-2-[4-(trifluoromethyl)pyrazol-1 -yl]acetamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4- d]pyrimidin-5-

229 +++

yl)phenyl]-2-[5-(trifluoromethyl)isoxazol-3-yl]acetamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4- d]pyrimidin-5-

230 +++

yl)phenyl]-2-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]aceta mide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4- d]pyrimidin-5-

231 yl)-2-methoxy-phenyl]-2-[1 -methyl-5-(trifluoromethyl)pyrazol-4- +++

yl]acetamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]p yrimidin-5-

232 +++

yl)phenyl]-2-[1 -methyl-5-(trifluoromethyl)pyrazol-4-yl]acetamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[4,5]pyrrolo[1 ,2-d]pyrimidin-5-

233 yl)-2-methoxy^henyl]-2-[2-methyl-4-(trifluoromethyl)imidazol -1 - ++

yl]acetamide

/V-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-d]pyrimidin-5 -yl)-2-

234 ++

methoxy-phenyl]-2-[5-(trifluoromethyl)isoxazol-3-yl]acetamid e

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4- d]pyrimidin-5-

235 +++ yl)-2-methoxy-phenyl]-2-[3-(trifluoromethyl)isoxazol-5-yl]ac etamide

/V-[4-(4-amino-6,8-dihydrofuro[4,5]pyrrolo[1 ,2-d]pyrimidin-5-yl)phenyl]-2-

236 +++

[4-(trifluoromethyl)imidazol-1 -yl]acetamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[4,5]pyrrolo[1 ,2-d]pyrimidin-5-

237 +++

yl)phenyl]-2-[4-(trifluoromethyl)imidazol-1 -yl]acetamide

/V-[4-(4-amino-6,8-dihydrofuro[4,5]pyrrolo[1 ,2-d]pyrimidin-5-yl)-2-

238 ++

methoxy-phenyl]-2-indazol-1 -yl-acetamide

/V-[4-(4-amino-6,8-dihydrofuro[4,5]pyrrolo[1 ,2-d]pyrimidin-5-yl)phenyl]-2-

239 ++

[3-(trifluoromethyl)pyrazol-1 -yl]acetamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4- d]pyrimidin-5-

240 +++

yl)phenyl]-2-[3-(trifluoromethyl)isoxazol-5-yl]acetamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4- d]pyrimidin-5-

241 +++ yl)-2-methoxy-phenyl]-2-[5-(difluoromethyl)isoxazol-3-yl]ace tamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]p yrimidin-5-

242 ++

yl)phenyl]-2-[5-(difluoromethyl)isoxazol-3-yl]acetamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4- d]pyrimidin-5-

243 ++

yl)phenyl]-2-(3-isopropyl-1 ,2,4-oxadiazol-5-yl)acetamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4- d]pyrimidin-5-

244 +++ yl)-2-methoxy-phenyl]-2-(3-isopropyl-1 ,2,4-oxadiazol-5-yl)acetamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[4,5]pyrrolo[1 ,2-d]pyrimidin-5-

245 +++

yl)-2-methoxy-phenyl]-2-(3-tert-butylpyrazol-1 -yl)acetamide A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]p yrimidin-5-

246 +

yl)phenyl]-2-[5-(trifluoromethyl)-1 ,3,4-oxadiazol-2-yl]acetamide

/V-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-d]pyrimidi n-5-yl)-2-

247 ++

methoxy-phenyl]-2-(2-tert-butylthiazol-4-yl)acetamide

/V-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-d]pyrimidi n-5-yl)-2-

248 ++

methoxy-phenyl]-2-(2-isopropylthiazol-4-yl)acetamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4- d]pyrimidin-5-

249 +++

yl)-2-methoxy-phenyl]-2-(2-isopropylthiazol-4-yl)acetamide

/V-[4-(4-amino-6,8-dihydrofuro[4,5]pyrrolo[1 ,2-d]pyrimidin-5-yl)-2-

250 ++

methoxy-phenyl]-2-(3-tert-butylpyrazol-1 -yl)acetamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[4,5]pyrrolo[1 ,2-d]pyrimidin-5-

251 +++

yl)phenyl]-2-(3-isopropylpyrazol-1 -yl)acetamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[4,5]pyrrolo[1 ,2-d]pyrimidin-5-

252 +++

yl)phenyl]-2-(3-cyclopropylpyrazol-1 -yl)acetamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[4,5]pyrrolo[1 ,2-d]pyrimidin-5-

253 +++

yl)phenyl]-2-(4-tert-butylpyrazol-1 -yl)acetamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[4,5]pyrrolo[1 ,2-d]pyrimidin-5-

254 +++

yl)-2-methoxy-phenyl]-2-(3-cyclopropylpyrazol-1 -yl)acetamide

/V-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-d]pyrimidi n-5-yl)-2-

255 + methoxy^henyl]-2-[1 -methyl-5-(trifluoromethyl)pyrazol-4-yl]acetamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4- d]pyrimidin-5-

256 +++

yl)-2-methoxy-phenyl]-2-(2-isopropyloxazol-4-yl)acetamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4- d]pyrimidin-5-

257 +++

yl)-2-methoxy-phenyl]-2-(2-tert-butyltetrazol-5-yl)acetamide

/V-[4-(4-amino-6,8-dihydrofuro[4,5]pyrrolo[1 ,2-d]pyrimidin-5-yl)phenyl]-2-

258 +++

(4-tert-butylpyrazol-1 -yl)acetamide

/V-[4-(4-amino-6,8-dihydrofuro[4,5]pyrrolo[1 ,2-d]pyrimidin-5-yl)-2-

259 ++

methoxy-phenyl]-2-(4-tert-butylpyrazol-1 -yl)acetamide

/V-[4-(4-amino-6,8-dihydrofuro[4,5]pyrrolo[1 ,2-d]pyrimidin-5-yl)phenyl]-2-

260 ++

(3-tert-butylpyrazol-1 -yl)acetamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]p yrimidin-5-

261 ++

yl)-2-methoxy-phenyl]-2-(4-tert-butylphenyl)acetamide

/V-[4-(4-amino-6,8-dihydrofuro[4,5]pyrrolo[1 ,2-d]pyrimidin-5-yl)-2-

262 +++

methoxy-phenyl]-2-(3-isopropylpyrazol-1 -yl)acetamide

A/ 4-(4-amino-6,8-clihydrofuro[2,3]pyrrolo[2,4-cl]pyrimiclin-5- yl)-2-methoxy-

263 +++

phenyl]-2-(3-fluoro-4-methyl-phenyl)acetamide

A/ 4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-cl]pyri miclin-5-yl)-2-

264 ++

methoxy-phenyl]-2-[5-(trifluoromethyl)pyridazin-3-yl]acetami de

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4- d]pyrimidin-5-

265 ++

yl)phenyl]-2-[1 -(difluoromethyl)pyrazol-4-yl]acetamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4- d]pyrimidin-5-

266 +++ yl)-2-methoxy-phenyl]-2-[1 -(difluoromethyl)pyrazol-3-yl]acetamide

/V-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]p yrimidin-5-

267 ++

yl)phenyl]-2-[1-(difluoromethyl)pyrazol-3-yl]acetamide

/V-[4-(4-amino-6,8-dihydrofuro[2,3]pyrrolo[2,4-d]pyrimidi n-5-yl)phenyl]-2-[1-

268 +

(difluoromethyl)pyrazol-3-yl]acetamide 2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[4,5]pyrrolo[1 ,2-d]pyrimidin-5-

269 ++ yl)-2-methoxy^henyl]-N-[2-(trifluoromethyl)pyrimidin-5-yl]ac etamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d ]pyrimidin-5-

270 ++ yl)-2-methoxy-phenyl]-N-[4-(3-hydroxyoxetan-3-yl)phenyl]acet amide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d ]pyrimidin-5-

271 yl)-2-methoxy-phenyl]-N-[5-(1 -hydroxy-1 -methyl-ethyl)-2- ++

pyridyl]acetamide

2-[4-(4-amino-6,8-dihydrofuro[4,5]pyrrolo[1 ,2-d]pyrimidin-5-yl)-2-

272 +

methoxy-phenyl]-N-phenyl-acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[4,5]pyrrolo[1 ,2-d]pyrimidin-5-

273 +++

yl)-2-methoxy-phenyl]-N-[4-(trifluoromethyl)thiazol-2-yl]ace tamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]py rimidin-5-

274 yl)-2-methoxy-phenyl]-N-(1 ,1 -dimethyl-3H-isobenzofuran-5- +++

yl)acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]py rimidin-5-

275 yl)-2-methoxy-phenyl]-N-[6-(1 -hydroxy-1 -methyl-ethyl)-3- +++

pyridyl]acetamide

2-[4-(4-amino-6,8-dihydrofuro[4,5]pyrrolo[1 ,2-d]pyrimidin-5-yl)-2-

276 +++

methoxy-phenyl]-N-[6-(trifluoromethyl)-3-pyridyl]acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d ]pyrimidin-5-

277 +++ yl)-2-methoxy-phenyl]-N-[5-(trifluoromethyl)pyridazin-3-yl]a cetamide

3-[[2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[4,5]pyrrolo[1 ,2-d]pyrimidin-

278 ++

5-yl)-2-methoxy-phenyl]acetyl]amino]-N-methyl-benzamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d ]pyrimidin-5-

279 yl)-2-methoxy-phenyl]-N-[6-(1 -methoxy-1 -methyl-ethyl)-3- +++

pyridyl]acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[4,5]pyrrolo[1 ,2-d]pyrimidin-5-

280 yl)-2-methoxy-phenyl]-N-[3-methoxy-5- +++

(trifluoromethyl)phenyl]acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[4,5]pyrrolo[1 ,2-d]pyrimidin-5-

281 +++

yl)-2-methoxy-phenyl]-N-(5-fluoro-6-methoxy-3-pyridyl)acetam ide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[4,5]pyrrolo[1 ,2-d]pyrimidin-5-

282 +++

yl)phenyl]-N-(5-fluoro-6-methoxy-3-pyridyl)acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d ]pyrimidin-5-

283 +++

yl)-2-methoxy-phenyl]-N-(2,1 ,3-benzoxadiazol-5-yl)acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d ]pyrimidin-5-

284 +++

yl)-2-methoxy-phenyl]-N-(4-tert-butylphenyl)acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d ]pyrimidin-5-

285 +

yl)-2-methoxy-phenyl]-N-(1 -methylpyrazol-4-yl)acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d ]pyrimidin-5-

286 +

yl)-2-methoxy-phenyl]-N-(1 -methylpyrazol-3-yl)acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d ]pyrimidin-5-

287 +

yl)-2-methoxy-phenyl]-N-(2-methylpyrazol-3-yl)acetamide

2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d ]pyrimidin-5-

288 +++

yl)-2-methoxy-phenyl]-N-(6-methoxypyridazin-3-yl)acetamide 2-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]py rimidin-5-

289 ++

yl)-2-methoxy^henyl]-N-[1 -(difluoromethyl)pyrazol-4-yl]acetamide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]p yrimidin-5-

290 +++

yl)-2-methoxy-phenyl]-2-[4-(3-hydroxyoxetan-3-yl)phenyl]acet amide

A/-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]p yrimidin-5-

291 yl)-2-(trifluoromethyl)phenyl]-2-[2-fluoro-5- +

(trifluoromethyl)phenyl]acetamide

[00873] The table below gives values for the IC50 of certain compounds of the invention.

[00874] Throughout the description and claims of this specification, the words "comprise" and "contain" and variations of them mean "including but not limited to", and they are not intended to (and do not) exclude other moieties, additives, components, integers or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

[00875] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

[00876] The reader's attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.